22 May 2014

EMA/369266/2014
Committee for Medicinal Products for Human Use (CHMP)

Translarna
(ataluren)
Procedure No. EMEA/H/C/002720
Applicant: PTC Therapeutics Limited

Assessment report for initial marketing authorisation application

Assessment report as adopted by the CHMP with

all commercially confidential information deleted

7 Westferry Circus Canary Wharf London E14 4HB United Kingdom

Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455
E-mail info@ema.europa.eu Website www.ema.europa.eu

An agency of the European Union

Table of contents
1. Background information on the procedure .............................................. 5
1.1. Submission of the dossier ....................................................................................5
1.2. Manufacturers ....................................................................................................6
1.3. Steps taken for the assessment of the product ........................................................6
1.4. Steps taken for the re-examination procedure.........................................................7
2. Scientific discussion ................................................................................ 8
2.1. Introduction .......................................................................................................8
2.2. Quality aspects ...................................................................................................9
2.2.1. Introduction ....................................................................................................9
2.2.2. Active Substance .............................................................................................9
2.2.3. Finished Medicinal Product ............................................................................... 11
2.2.4. Discussion on chemical, pharmaceutical and biological aspects ............................. 13
2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 13
2.2.6. Recommendation(s) for future quality development ............................................ 13
2.3. Non-clinical aspects........................................................................................... 13
2.3.1. Introduction .................................................................................................. 13
2.3.2. Pharmacology ................................................................................................ 13
2.3.3. Pharmacokinetics ........................................................................................... 17
2.3.4. Toxicology .................................................................................................... 18
2.3.5. Ecotoxicity/environmental risk assessment ........................................................ 21
2.3.6. Discussion on non-clinical aspects .................................................................... 21
2.3.7. Conclusion on the non-clinical aspects ............................................................... 23
2.4. Clinical aspects ................................................................................................. 24
2.4.1. Introduction .................................................................................................. 24
2.4.2. Pharmacokinetics ........................................................................................... 25
2.4.3. Pharmacodynamics ........................................................................................ 27
2.4.4. Discussion on clinical pharmacology .................................................................. 28
2.4.5. Conclusions on clinical pharmacology ................................................................ 30
2.5. Clinical efficacy ................................................................................................. 30
2.5.1. Dose response studies .................................................................................... 30
2.5.2. Main study .................................................................................................... 31
2.5.3. Discussion on clinical efficacy ........................................................................... 46
2.5.4. Conclusions on the clinical efficacy.................................................................... 51
2.6. Clinical safety ................................................................................................... 51
2.6.1. Discussion on clinical safety ............................................................................. 58
2.6.2. Conclusions on the clinical safety...................................................................... 60
2.7. Pharmacovigilance ............................................................................................ 60
2.8. Risk Management Plan....................................................................................... 60
2.9. User consultation .............................................................................................. 70

3. Benefit-Risk Balance ............................................................................. 70

4. Recommendations ................................................................................. 76
4.1. Risk Management Plan....................................................................................... 82
5. Benefit-Risk Balance ............................................................................. 94
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List of abbreviations
6MWD
6MWT
AUC
ACTH
ALT
ANCOVA
AP
AST
BCRP
BCS
BID
BUN
CF
CFTR
Chol
cITT
CK
CNS
ECG
EC
EU
DBMD
DMC
DMD
DMF
DMSO
DNA
DSC
EC
EU
F
GC
GCP
GLP
Gluc
GMP
GRAS
Hb
Hct
HDPE
HEK293
hERG
HPLC
HRQL
ICH
IP
IR
ITT
IVR/IWR
KF
LD50
LOCF
LOEL
M
MCH
MCHC
MCID
MCV
MEFs
MMRM
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6-minute walking distance

6-minute walking test
area under curve
adrenocorticotrophic hormone
alanine aminotransferase
analysis of covariance
alkaline phosphatase
aspartate aminotransferase
breast cancer resistant protein
biopharmaceutics classification system
twice a day
blood urea nitrogen
cystic fibrosis
cystic fibrosis transmembrane conductance regulator
cholesterol
corrected intention to treat (population)
creatine kinase
central nervous system
electrocardiogram
European Commission
European Union
Duchenne/Becker muscular dystrophy
data monitoring committee
Duchenne muscular dystrophy
N,N-dimethylformamide
dimethylsulfoxide
deoxyribonucleic acid
differential scanning calorimetry
European Commission
European Union
female
gas chromatography
Good Clinical Practice
Good Laboratory Practice
Glucose
Good Manufacturing Practice
generally recognised as safe
haemoglobin
haematocrit
high density polyethylene
human embryonic kidney (cells)
human ether-a-go-go related gene
high performance liquid chromatography
health-related quality of life
International Conference on Harmonization (of technical requirements for
registration of pharmaceuticals for human use)
intraperitoneal
infra-red spectroscopy
intention-to-treat (population)
interactive voice response/interactive web response (system)
Karl-Fischer titration
lethal dose, 50%
last observation carried forward
low-observed-effect level
male
mean corpuscular haemoglobin
mean corpuscular haemoglobin concentration
minimal clinically important difference
mean corpuscular volume
mouse embryonic fibroblasts
mixed-model repeated-measures
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mRNA
nm
NMR
NOEL
NOAEL
OAT
PBMC
PBT
PCR
PD
PE
PedsQL
Ph. Eur.
PIB
PK
PPI
PTT
QC/QA
RBC
RH
RMP
RNA
ROI
SAE
SAP
SmPC
TFTs
TGA
TID
TSQM
UGT
UV
Vss
WBC
XRPD

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messenger ribonucleic acid

non-sense mutation
nuclear magnetic resonance spectroscopy
No-observed-effect level
No-observed-adverse-effect level
organic anion transporter
peripheral blood mononuclear cells
persistent, bioaccumulative and toxic
polymerase chain reaction
pharmacodynamics
polyethylene
paediatric quality of life
European Pharmacopoeia
powder in bottle
pharmacokinetics
proton pump inhibitors
partial thromboplastin time
quality control/quality assurance
red blood cells
relative humidity
risk management plan
ribonucleic acid
residue on ignition
serious adverse event
statistical analysis plan
summary of product characteristics
timed function tests
thermogravimetric analysis
three times a day
Treatment Satisfaction Questionnaire for Medication
uridine diphosphate glucuronosyltransferase
ultra-violet spectroscopy
volume of distribution at steady state
white blood cells
X-ray powder diffraction

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1. Background information on the procedure

1.1. Submission of the dossier
The applicant PTC Therapeutics Limited submitted on 29 October 2012 an application for
Marketing Authorisation to the European Medicines Agency (EMA) for Translarna, through the
centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No
726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 19
April 2012.
The applicant applied for the following indication:
Treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin
gene, in patients aged 5 years and older
The presence of a nonsense mutation in the dystrophin gene should be determined by genetic
testing.
Translarna was designated as an orphan medicinal product EU/3/05/278 on 27 May 2005.
Translarna was designated as an orphan medicinal product in the following indication: Treatment
of Duchenne muscular dystrophy.
Following the CHMP positive opinion on this marketing authorisation, the Committee for Orphan
Medicinal Products (COMP) reviewed the designation of Translarna as an orphan medicinal product
in the approved indication. The outcome of the COMP review can be found on the Agency's
website: ema.europa.eu/Find medicine/Rare disease designations.
The legal basis for this application refers to:
Article 8.3 of Directive 2001/83/EC - complete and independent application. The applicant
indicated that ataluren was considered to be a new active substance.
The application submitted is composed of administrative information, complete quality data, nonclinical and clinical data based on applicants own tests and studies and/or bibliographic literature
substituting/supporting certain tests or studies.
Information on Paediatric requirements
Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision
P/0202/2012 on the agreement of a paediatric investigation plan (PIP).
At the time of submission of the application, the PIP P/0202/2012 was not yet completed as some
measures were deferred.
Information relating to orphan market exclusivity

Similarity
Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation
(EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity
with authorised orphan medicinal products because there is no authorised orphan medicinal
product for a condition related to the proposed indication.
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Applicants request(s) for consideration

Conditional Marketing Authorisation
The applicant requested consideration of its application for a Conditional Marketing Authorisation
in accordance with Article 14(7) of the above mentioned Regulation based on the following
claim(s):
-

The product will address unmet medical need in a life-threatening and chronically
debilitating condition where no satisfactory methods of treatment exist.

The risk-benefit balance of the product is positive.

The benefits to public health of the immediate availability outweigh the risks inherent in
the fact that additional data are still required.

It is likely that the Applicant will be able to provide comprehensive data based on
confirmatory study in nmDMD patients.

New active Substance status

The applicant requested the active substance ataluren contained in the above medicinal product
to be considered as a new active substance in itself, as the applicant claims that it is not a
constituent of a product previously authorised within the Union.
Protocol Assistance
The applicant received Protocol Assistance from the CHMP on 19 July 2007 and on 24 May 2012.
The Protocol Assistance pertained to clinical aspects of the dossier.
Licensing status
The product was not licensed in any country at the time of submission of the application.

1.2. Manufacturers
Manufacturer responsible for batch release
Almac Pharma Services Ltd.
Seagoe Industrial Estate
Craigavon
Co. Armagh BT63 5UA
United Kingdom

1.3. Steps taken for the assessment of the product

The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were:
Rapporteur: Johann Lodewijk Hillege
Co-Rapporteur: Concepcion Prieto Yerro
CHMP Peer reviewer: Ian Hudson
The EMA Product Team Leader: Viktor Vlcek

The application was received by the EMA on 29 October 2012.

The procedure started on 21 November 2012.

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The Rapporteur's first Assessment Report was circulated to all CHMP members on 12

February 2013. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members
on 9 February 2013.

During the PRAC meeting on 4-7 March 2013, the PRAC adopted an RMP Advice and

assessment overview.

During the meeting on 21 March 2013, the CHMP agreed on the consolidated List of

Questions to be sent to the applicant. The final consolidated List of Questions was sent to the
applicant on 25 March.

The applicant submitted the responses to the CHMP consolidated List of Questions on 23

July 2013.

The Integrated Inspection Report (IIR) of the inspections carried out at the following

site(s): Clinical Investigator sites in UK and USA, Sponsor site in USA and Central Pathology lab in
USA, between 2 April and 7 May 2013 was issued on 5 July 2013.

The Rapporteurs circulated the Joint Assessment Report on the applicants responses to

the List of Questions to all CHMP members on 29 August 2013.

During the PRAC meeting on 2-5 September 2013, the PRAC adopted an RMP assessment

report.

During the CHMP meeting on 19 September 2013, the CHMP agreed on a list of

outstanding issues to be addressed in writing and/or in an oral explanation by the applicant.

The applicant submitted the responses to the CHMP List of Outstanding Issues on 21

October 2013.

The Rapporteurs circulated the Joint Assessment Report on the applicants responses to

the List of Outstanding Issues to all CHMP members on 5 November 2013.

During the PRAC meeting on 4-7 November 2013, the PRAC adopted an RMP assessment

report.

During a meeting of a SAG on 5 December 2013, experts were convened to address

questions raised by the CHMP.

During the PRAC meeting on 2-5 December 2013, the PRAC adopted an RMP Advice and

assessment overview.

During the CHMP meeting on 17 December 2013, outstanding issues were addressed by

the applicant during an oral explanation.

During the meeting on 23 January 2014, the CHMP, in the light of the overall data

submitted and the scientific discussion within the Committee, issued a negative opinion for
granting a Marketing Authorisation to Translarna.

1.4. Steps taken for the re-examination procedure

The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were:
Rapporteur:

Martina Weise

Co-Rapporteur: Greg Markey

EMA Product Team Leader:

Viktor Vlcek

The applicant submitted written notice to the EMA on 28 January 2014 to request a
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re examination of Translarna CHMP opinion of 23 January 2014.

During its meeting on 17-20 February 2014, the CHMP appointed Martina Weise as

Rapporteur and Greg Markey as Co-Rapporteur.

The applicant submitted the detailed grounds for the re-examination on 25 March 2014.

The re-examination procedure started on 26 March 2014.

The Rapporteur's Assessment Report was circulated to all CHMP members on

17 April 2014. The Co Rapporteur's Assessment Report was circulated to all CHMP members on 22
April 2014.

The Rapporteurs circulated the Joint Assessment Report on the applicants detailed

grounds for re-examination to all CHMP members on 8 May 2014.

During the CHMP meeting on 19-22 May 2014, the detailed grounds for re-examination

were addressed by the applicant during oral explanations before the CHMP.

During the meeting on 19-22 May 2014, the CHMP, in the light of the scientific data

available and the scientific discussion within the Committee, the CHMP re-examined its initial
opinion and in its final opinion concluded that the application satisfied the criteria for authorisation
and recommended the granting of the conditional marketing authorisation.

2. Scientific discussion
2.1. Introduction
Duchenne muscular dystrophy (DMD) is a rare (1 in 3500 male newborns), disabling and ultimately
fatal X-linked genetic disorder that primarily affects males [Emery 1991, Worton 2001, Khurana
2003]. The disease is caused by mutations in the gene for dystrophin, a protein that is critical to
the structural stability of myofibers in skeletal, diaphragmatic and cardiac muscle and is also of
importance for the central nervous system and smooth muscles [Worton 2001, Khurana 2003].
DMD is caused by several types of mutations in the dystrophin gene such as deletions, insertions
and point mutations. Approximately 13% of patients with DMD have the disorder due to a
nonsense mutation [Dent 2005]. A nonsense mutation is a change in the nucleotide sequence of
DNA that is transcribed into a premature stop codon in the messenger RNA (mRNA) for dystrophin.
This stop codon causes the ribosome complex to terminate translation prematurely and results in a
truncated, non-functional protein.
The overall prevalence of DMD in the European Union (EU) is of the order of 0.37 per 10,000
[Orphanet 2011], accounting for approximately 18,600 individuals (current EU population
estimated at 503,500,000) [Eurostat 2012]. Based on the estimation that in about 13% of all DMD
patients the disease is due to a nonsense mutation (nmDMD) [Dent 2005], it is estimated that
there are approximately 2,400 patients with nmDMD in the EU.
The majority of genetic defects in subjects with Duchenne and Becker muscular dystrophy are large
deletions or insertions in the dystrophin gene. Point mutations leading to a nonsense codon are
relatively rare and are found in about 7-13% of the DMD/BMD patient population. In DMD the
disease is caused by the lack of a functional dystrophin - a structural protein from the sarcoglycan
complex important for stability of skeletal and cardiac muscle cell, but also expressed in the CNS
and smooth muscle. The concept of treating DMD subjects with a nonsense mutation is to promote
production of a full-length dystrophin protein and hence restore its function in muscle cells.

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There are no curative therapies available for DMD and the current management of the disease is
based on prevention and management of complications [Bushby 2010]. Corticosteroids (e.g.
prednisone or deflazacort) are the only pharmacologic therapy that have been demonstrated

to

temporarily reduce the decline in motor function in patients with DMD [Mendell 1989, Griggs 1991,
Fenichel 1991a, Fenichel 1991b, Biggar 2001, Beenakker 2005a, Biggar 2006, Pradhan 2006].
Ataluren is a first-in-class oral drug which is claimed to enhance ribosomal read-through of nonsense mutations in different genes. The mode of action of ataluren is believed to be related to the
ability of this compound to interfere with the ribosomal translational machinery in such a way that
premature nonsense stop codons in the mRNA are read through by the translational machinery and
this results in the translation of the entire mRNA and hence production of a full-length protein
product.
The applicant applied for the following indication:
Translarna is indicated for the treatment of Duchenne muscular dystrophy resulting from a
nonsense mutation in the dystrophin gene, in patients aged 5 years and older (see section 5.1).
The presence of a nonsense mutation in the dystrophin gene should be determined by genetic
testing (see section 4.4).
The recommended dose of ataluren is 40 mg/kg/day, divided in 3 doses (10 mg/kg in the morning,
10 mg/kg at midday and 20 mg/kg in the evening) within 30 minutes of a meal.

2.2. Quality aspects

2.2.1. Introduction
The finished product is presented as granules for oral suspension containing 125, 250, or 1000
mg of Ataluren as active substance.
Other ingredients are: Polydextrose (E1200), polyethylene glycol, poloxamer, mannitol (E421),
crospovidone, hydroxyethyl cellulose, artificial vanilla flavour, colloidal silicon dioxide (E551) and
magnesium stearate.
The product is available in child-resistant heat-sealed laminated aluminium foil sachets.

2.2.2. Active Substance

The chemical name of Ataluren is 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]-benzoic acid and
has the following structure:

The structure of Ataluren was unambiguously confirmed by 1H and

13

C NMR, UV spectroscopy, IR

spectroscopy, mass spectrometry and elemental analysis. Physical properties were investigated
using DSC, TGA, XRPD, KF (to determine water content and hygroscopicity) and particle size
distribution.

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Ataluren is a white to off-white non-hygroscopic crystalline solid, practically insoluble in pH 1 and

sparingly soluble at pH 6.6 in aqueous medium. Solubility is much higher in aqueous borate buffer
at pH 8 due to the carboxylic acid functionality. Ataluren is also slightly soluble in acetonitrile and
ethanol and freely soluble in DMSO, 1,4-dioxane and DMF. Although dosed as a suspension, the
active substance is milled to increase solubility in vivo.
Ataluren is achiral. Polymorphism has been observed for Ataluren. The most thermodynamically
stable form is routinely made by the proposed manufacturing process.
Manufacture
Ataluren is synthesized from well-defined starting materials with acceptable specifications. Enough
of the manufacturing process is described and the physicochemical properties of the active
substance are well controlled by the process. A particle size reduction step is required to ensure
robust dissolution following formulation. Detailed information about the manufacturing process and
process development has been provided. Since the manufacturing process is considered as
standard, validation will be performed ahead of release of commercial supplies. A validation
protocol was provided. Separate manufacturing sites are used which carry out identical processes
with the exception of differences in scale.
The manufacturing process is adequately described. The characterisation of the active substance
and its impurities are in accordance with the EU guideline on chemistry of new active substances.
Potential and actual impurities were well discussed with regards to their origin and characterised.
Impurities present at higher than the qualification threshold according to ICH Q3A were qualified
by toxicological and clinical studies and appropriate specifications have been set.
All relevant impurities, including genotoxins, degradation products, by-products derived from
impurities in the starting materials, synthetic intermediates, reaction by-products and residual
solvents have been appropriately characterised and are controlled by the active substance
specifications. Sufficient information on two genotoxic impurities is provided and these are
controlled well below the TTC limit. The overall control strategy is traditional and includes
adherence to process description parameters, a series of in-process controls during each synthetic
step, appropriate specifications for starting materials, intermediates, solvents and reagents, and
active substance release testing. Therefore, the manufacturer has good control over the
manufacturing process and the described control strategy is considered adequate to ensure the
required quality active substance.
Specification
The active substance specification includes tests for appearance, identity (IR), assay (HPLC),
impurities (HPLC), residual solvents (GC), water content (KF), heavy metals (Ph. Eur.), residue on
ignition (Ph. Eur.) and particle size distribution (laser diffraction).
The analytical methods used have been adequately described and non-compendial methods
appropriately validated in accordance with the ICH guidelines.
Batch analysis data from 21 batches of active substance from the proposed manufacturers on
commercial scale are provided. Batch analysis on a further 11 batches ranging from development
scale to commercial scale from a previous (no longer used) manufacturer are also provided as
supporting data. The results are within the specifications and consistent from batch to batch.
Stability
Stability data on three commercial batches of active substance from one proposed manufacturer,
and three pilot scale batches from the other proposed manufacturer, stored in the intended
commercial package for up to 48 months under long term conditions at 25 C / 60% RH and for
up to 6 months under accelerated conditions at 40 C / 75% RH according to the ICH guidelines
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were provided. Additionally, stability data on six additional pilot scale batches of active substance
from a previous (no longer used) manufacturer stored in the intended commercial package for up
to 60 months under long term conditions at 25 C / 60% RH and for up to 6 months under
accelerated conditions at 40 C / 75% RH according to the ICH guidelines were provided as
supportive data. No changes to any of the measured parameters were observed over the course
of the studies under either long term or accelerated conditions.
The active substance was also exposed to thermal, humidity, photolytic, acidic, basic, and
oxidative stress conditions following ICH guideline Q1B. These studies further establish the
stability of Ataluren and demonstrate that the analytical methods are stability indicating.
The parameters tested are the same as for release with the omission of those unaffected by
storage (heavy metals, ROI and residual solvents) and the addition of microbial testing. The
analytical methods used were the same as for release.
The stability results indicate that the drug substance manufactured by the proposed suppliers is
sufficiently stable. The stability results justify the proposed retest period in the proposed
container.

2.2.3. Finished Medicinal Product

Pharmaceutical development
The objectives of formulation development were to develop an immediate release solid oral
dosage form of Ataluren suitable for consumption by paediatric patients and young adults. After
initial clinical studies using powder in bottle formulation, granules for suspension were selected as
the commercial dosage form since these would allow reconstitution in liquid media (water, milk,
fruit juice) or semi-solid media (yoghurt, pudding, or apple sauce) for ease of administration to
the youngest patients.
The active substance shows pH dependent dissolution characteristics due to the ionisable
carboxylic acid group, being practically insoluble in acidic or neutral pH and soluble in basic
aqueous media. It has been shown to be highly permeable in in vitro assays (BCS class II).
Ataluren has a bitter taste. Excipients were chosen to improve powder flow properties for large
scale granulation, to aid formation of a homogeneous suspension given the poor wetting
properties of the active substance, and to mask the active substance taste.
All excipients are well known pharmaceutical ingredients or food additives and their quality is
compliant with Ph. Eur. standards, tested to be suitable for pharmaceutical use, or generally
recognised as safe (GRAS). There are no novel excipients used in the finished product
formulation. The full list of excipients is included in section 6.1 of the SmPC.
Compatibility studies between active substance and a range of potential excipients tested in
formulation development were carried out under accelerated conditions (40 C / 75% RH) over 12
weeks. The active substance was shown to be compatible with all tested excipients.
The granules are stored in moisture-excluding aluminium sachets to prevent clumping of the
granules over time.
The formulation evolved during development from a powder to granules, which is also the
commercial formulation. Comparative dissolution data indicate that all previously used clinical
formulations and the commercial formulation have similar dissolution profiles, with >85%
dissolution in <15 minutes. The discriminatory power of the dissolution method has been
demonstrated.

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The primary packaging is child-resistant heat-sealed laminated aluminium foil sachets. The
material complies with Ph. Eur. and EC requirements. The choice of the container closure system
has been validated by stability data and is adequate for the intended use of the product.
Adventitious agents
No excipients derived from animal or human origin have been used in the formulation. Magnesium
stearate is derived from a vegetable source.
Manufacture of the product
The manufacturing process is considered standard for the production of granules. Key steps in the
process include roller compaction, milling and blending. Adequate process controls are in place for
each of these steps to ensure the quality of the finished product. The formal validation of the
process in the production facilities has not yet been completed but will be carried out prior to
release of Translarna to the market. A process validation scheme has been provided and the
applicant will validate the process before commercialisation.
Product specification
The finished product release specifications include validated tests for appearance (visual
description), identification (HPLC and UV), assay (HPLC), degradants (HPLC) content uniformity
(HPLC), dissolution (HPLC), water content (KF) and microbial limits (Ph. Eur.) appropriate for this
kind of dosage form.
Batch analysis results are provided for three batches of 125 mg strength, nine batches of 250 mg
strength and four batches of 1000 mg strength, confirming the consistency and uniformity of the
manufacturing process and its ability to manufacture the finished product to the intended
specifications.
Stability of the product
A bracketing strategy was used to investigate stability: the 125 mg and 1000 mg strengths were
tested but not the intermediate 250 mg strength. This is considered acceptable. Stability data
from three commercial scale batches of both 125 mg and 1000 mg strengths of finished product
stored under long term conditions (25 C / 60% RH) for 48 months, under intermediate
conditions (30 C / 75% RH) for 36 months at and for up to 6 months under accelerated
conditions (40 C / 75% RH) according to the ICH guidelines were provided. The batches of
Translarna were identical to those proposed for marketing and were packed in the primary
packaging proposed for marketing.
In addition, finished product in the proposed commercial packaging was exposed to light as
defined in the ICH Guideline on Photostability Testing of New Drug Substances and Products.
Samples were tested for appearance, assay, degradants, dissolution, moisture content, microbial
limits, granule particle size and average deliverable powder weight. The analytical procedures
used are stability indicating.
None of the parameters tested showed any observable trends over the course of the stability and
photostability studies.
Since finished product granules can be reconstituted in liquid media (water, milk, fruit juice) and
semi-solid media (yoghurt, pudding, apple sauce), in-use stability data have been provided which
indicate the preparation in water at ambient conditions or that in other liquid or semi-solid media
under refrigerated conditions should be used within 24 hours. The stability data also supports
transient excursion to room temperature for 3 hours in milk or yoghurt or 6 hours in fruit juice,
pudding, or apple sauce.

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Based on available stability data, the shelf-life and storage conditions as stated in the SmPC are
acceptable.
The applicant will conduct stability studies on the first 3 commercial production batches under
long-term (25 C / 60% RH) and accelerated (40 C / 75% RH) conditions, and 1 commercial
production batch per year thereafter.

2.2.4. Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of the active substance and finished
product has been presented in a satisfactory manner. The results of tests carried out indicate
consistency and uniformity of important product quality characteristics, and these in turn lead to
the conclusion that the product should have a satisfactory and uniform performance in clinical
use.

2.2.5. Conclusions on the chemical, pharmaceutical and biological

aspects
The quality of this product is considered to be acceptable when used in accordance with the
conditions defined in the SmPC. Physicochemical and biological aspects relevant to the uniform
clinical performance of the product have been investigated and are controlled in a satisfactory
way.

2.2.6. Recommendation(s) for future quality development

Not applicable.

2.3. Non-clinical aspects

2.3.1. Introduction
Ataluren (PTC124) is an orally bioavailable small molecule intended for the treatment of Duchenne
muscular dystrophy resulting from a nonsense mutation in the dystrophin gene. Ataluren is the
first investigational new drug designed to enable ribosomal readthrough of premature stop codons,
resulting in the formation of a full-length functional protein in patients with nonsense mutation
genetic disorders.
The summary of the pharmacology, pharmacokinetics and toxicology of ataluren provided below is
based on the non-clinical summary submitted by the Applicant and available information on the
published scientific literature.
Safety pharmacology studies and all pivotal toxicity studies were performed under GLP.

2.3.2. Pharmacology
Primary pharmacodynamic studies
A series of in vitro studies were conducted in different model systems to characterise the primary
pharmacodynamics of ataluren. In HEK293 cells transfected with the luciferase gene engineered to
have premature stop codons at codon 190, increasing concentrations of ataluren resulted in dose-

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dependent readthrough of full-length, functional luciferase as measured by chemiluminescence in

the HEK293 LUC-190 cell-based assays (Fig. 1).
Fig. 1

A dose-dependent readthrough and production of full-length, functional luciferase was also seen in
a cell-free translation assay (LUC-190 mRNA with a cytoplasmic translation extract from HeLa cells
(Fig. 2).

Fig. 2

In myotubes isolated from the mouse model of nonsense mutation DMD (mdx mice) testing
ataluren concentrations of 0.1 to 30 g/ml and in cultured human myotubes from nmDMD patients
testing concentrations of 0.1 to 40 g/ml, a bell-shaped dose response was observed, with
maximal induction of dystrophin at an ataluren concentration of 10 g/ml.
In mouse embryonic fibroblasts (MEFs) isolated from the mouse model of nonsense mutation
Hurler syndrome (Idua-W392X mice), reduction in tissue glycosaminoglycan levels due to
production of a full-length functional enzyme was evaluated. The maximal induction of enzyme
activity was seen at an ataluren concentration of 10 g/ml, indicating a bell-shaped response.
The ability of ataluren to read through premature stop codons, thus enabling production of full
length functional protein, was further investigated in vivo in nonsense mutation mouse models:
nmDMD mdx mice, Cftr-/- FABP-hCFTR-G542X mice (a mouse model of nonsense mutation cystic
fibrosis) and Idua-W392X mice (a mouse model of nmHurler syndrome).

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In the mdx mouse model of nmDMD testing three dosing regimens- oral, intraperitoneal (IP) and
combination of both, the optimal efficacy was observed with a combined oral and IP dosing (1.8
mg/ml via a liquid diet and 33 mg/kg IP TID). Pharmacokinetics were performed and this dosing
regimen resulted in a trough concentration of approximately 10 g/ml. Doses that would result in
higher plasma concentrations were not assessed and the potential for a bell-shaped response could
not be determined in this model. Overall, ataluren administration resulted in protection from
eccentric contraction injury and in reduced serum CK, indicating reduced muscle fragility.
Dystrophin was seen to be located in the cell appropriately, with levels accounting to 20% of the
normal levels.
During the procedure, the Applicant submitted additional data from an nmDMD zebrafish model
indicating promotion of nonsense mutation readthrough (fig. 3).
Fig. 3 Effect of ataluren treatment on dystrophin expression in nmDMD zebrafish model
Wild-type

untreated

ataluren

Li, et al, In Press

In an in vivo model of CF (Cftr-/-FABP-hCFTR-G542X mice) ataluren administration dosedependently increased expression of appropriately located full-length CFTR and restored CFTRdependent chloride channel function. When ataluren was administered to Idua-W392X mice, a bellshaped dose response was observed with maximal induction of Idua enzyme activity at an ataluren
dose of 0.1% (in brain, spleen, heart, and lung) or 0.3% (3.7 to 19 g/ml) (in liver), with less
activity at 1.0% (w/w).
Secondary pharmacodynamic studies
In an RT-PCR assay, LUC-190 (UGA) mRNA transcripts were monitored to determine whether
ataluren might affect cellular mRNA levels. Data obtained with HEK293 LUC-190 (UGA) cells
incubated with ataluren at a concentration of 30 M showed that LUC-190 mRNA levels were not
altered. In a microarray analysis of mRNA levels assessing the effect of ataluren treatment, some
transcripts (22 out of >54000) were different from control cells at an ataluren concentration of 5
M. Results of both analyses indicated that ataluren did not globally affect the synthesis or stability
of the mRNA at concentrations that enable readthrough of a premature stop codon.
A series of studies was conducted, both in vitro and in vivo to evaluate the potential of ataluren to
promote readthrough of normal stop codons.
In a nonsense mutation luciferase-CD40 reporter assay, no readthrough of normal stop codons was
seen at any of the ataluren concentrations tested (fig. 4)

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Fig. 4

Similarly, no readthrough of normal stop codons was observed in a wild-type luciferase-CD40

reporter assay, with the normal UAA luciferase stop codon changed to a UGA stop codon. This was
documented by the absence of the luciferase-CD40 extended protein product in cells treated with
ataluren at concentration of 1, 10 and 100 M.
In a 2D gel analysis of ataluren effect on normal stop codons, HEK293 LUC-190 (UGA) cells were
incubated with ataluren at a concentration of 5 M. The only noted difference in the electrophoretic
pattern of proteins from cells incubated with ataluren compared to those from vehicle treated cells
was a protein with a molecular weight and charge corresponding to the luciferase protein. No
aberrantly elongated proteins were produced.
In order to evaluate the potential for off-target pharmacologic activity, evaluation of the ability of
ataluren to block binding of ligand to 62 diverse receptors or enzymes (neurotransmitter receptors,
enzymes, steroids, ion channels, secondary messengers, prostaglandins, growth factors or
hormones and brain and gut peptides) was conducted. Ataluren did not significantly block ligand
binding to any of the targets (inhibition of >50% was considered significant) at concentrations of
10 M (2.84 g/mL) and 30 M (8.52 g/mL).
Safety pharmacology programme
Ataluren was evaluated in stand-alone and GLP-compliant safety pharmacology studies.
The effects of ataluren on general activity and behaviour in the rat were evaluated at several timepoints after a single oral dose and after 7 consecutive daily doses of vehicle or 500, 1000 or 2000
mg/kg/day of ataluren. There were no behavioural or physiological changes in rats when compared
to vehicle control rats. A slight decrease (5%) in body weight on Day 2 was observed in the 2000
mg/kg/day dose group.
The effects on respiratory parameters of ataluren in single oral doses up to 2000 mg/kg were
evaluated in rat. Ataluren did not elicit any statistically significant or biologically important changes
in respiratory parameters of tidal volume, respiratory rate and minute volume.
The potential for effects on cardiovascular function were evaluated in vitro in a human ether-agogo-related gene (hERG) assay and in vivo, in a single dose cardiovascular safety pharmacology
study in telemetered dogs (in doses up to 1500 mg/kg) and the 4-week and 52-week toxicology
studies in dogs (in doses up 1500 and 1000 mg/kg/day, respectively). All studies were conducted
in accordance with GLP. In vitro, ataluren inhibited hERG current by 0.20.1% at 10 M and
4.10.1% at 100 M. In the in vivo studies in dogs, ataluren had no effect on the ECG
morphology, heart rate and ECG intervals at any dose.
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Pharmacodynamic drug interactions

The potential pharmacodynamic interaction of ataluren and representative aminoglycoside
antibiotics was explored in an in vitro model system of ribosomal readthrough. The ability of
ataluren to enable readthrough was reduced in the presence of antibiotics that are known to
interact with ribosomal RNA (gentamicin and tobramycin) but not in the presence of antibiotics that
act through alternative mechanisms (aztreonam and colistin).

2.3.3. Pharmacokinetics
The pharmacokinetic characteristics of ataluren were characterised after single- and repeat-dose
administration in mice. The toxicokinetics of ataluren were assessed after single- and repeat-dose
administration to animal species used in the toxicological evaluation, i.e. Tg.rasH2 wild type mice,
rats, dogs and rabbits.
Following oral administration of ataluren to mice, rats, dogs and rabbits, the drug was rapidly
absorbed and eliminated in all species, with peak concentrations after single doses occurring 0.25
to 4 hours post dose. The Tmax tended to increase with increasing dose and with multiple doses.
The half-life was similar across the non-clinical species tested and ranged within 1.1 to 7.6 hours.
There was no accumulation of drug in plasma upon repeated daily dosing. In rats, two peak plasma
concentrations were observed, indicating entero-hepatic recirculation. Plasma exposure to ataluren
in all species, based on Cmax and AUC, was less than dose proportional. After multiple dosing,
plasma exposure (in particular the AUC values) decreased after Day 1. Ataluren showed a high
plasma protein binding (98.4% in mouse, 98.7% in rat and 97.5 in dog).
Following intravenous administration of a single dose to dogs, the systemic clearance averaged 123
ml/kg.hr and the volume of distribution at steady state (Vss) was 0.21 l/kg. In a bioavailability
study conducted in dogs with intravenous and oral dosing, low bioavailability (7%) was seen, which
corresponded to the observed low urinary excretion in this species (12% of the dose). In mice and
rats, the excretion via urine and bile indicated high bioavailability (40% urinary excretion in mice
and 90% urinary and bile excretion in rats).
After oral administration of radio-labelled ataluren to rats, high concentrations were found in the
gastrointestinal tract, the secretion organs (liver and kidney), adrenal gland, brown fat and lung.
Low radioactivity concentrations were observed in the brain. The blood-to-plasma ratio of ataluren
radioactivity was less than one, indicating that ataluren does not accumulate in erythrocytes. At 24
hours after dosing, radioactivity was still observed in brown fat, skin and the Harderian and
preputial glands.
In rats, placental transfer of radio-labelled ataluren and excretion in milk were observed. At a
single maternal dose of 30 mg/kg, the concentration of foetal radioactivity was 27% of the
maternal concentration. At the same maternal dose, the highest measured concentration of
radioactivity in rat milk was 37% of the maternal plasma concentration. Presence of radioactivity in
pup plasma confirmed absorption from the milk by the pups. The composition of this radioactivity
(parent compound and/or metabolites) was not investigated.
The major biotransformation pathway of ataluren included acyl glucuronidation, reductive
oxadiazole ring cleavage, oxidative deamination and hydrolysis. In all species, unchanged ataluren
was the major component in plasma (ranging from 70 to 91%).
Ataluren was not metabolised by CYP isozymes, but was directly glucuronidated via UGT1A9 in
human liver microsomes. No non-clinical studies were performed by the applicant to evaluate
potential drug-drug interaction, but based on the in vitro data, inhibitors of UGT1A9 or drugs
metabolised by UGT1A9 may have a clinically relevant effect on the metabolism of ataluren.
In vitro studies indicated that ataluren was not a substrate for P-glycoprotein.
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Following a single oral dose of radio-labelled ataluren, the majority of the administered
radioactivity was excreted in faeces: 54% by mice, 84% by rats and 80% by dogs. Most of the
dose was excreted within 48 hours. The total recovery was >93% in the three species.

2.3.4. Toxicology
Single dose toxicity
Single dose toxicity studies of ataluren were conducted in rats and dogs. The oral LD50 in rats was
>2000 mg/kg, the highest dose tested. In an oral escalating dose study in dogs, ataluren was well
tolerated up to the highest dose of 1600 mg/kg. No macroscopic abnormalities were noted at
necropsy.
Repeat dose toxicity
Repeat dose toxicity studies of ataluren were conducted in mice for up to 29 days, in rats for up to
26 weeks and in dogs for up to 52 weeks. Both 26-week toxicology studies in rats and the 52-week
toxicology study in dogs initiated dosing in weanling animals to support dosing in children.
The major findings are summarised in Table 1.
Study

Species/Sex/

ID

Number/Group

Dose/ Route

Duration

NOEL/

Major findings

NOAEL
(mg/
kg/
day)

AB19L
A.2G3
R.04.B
TL
(GLP)

CByB6F1
(Tg.rasH2 nontransgenic
littermates)
hybrid mice
Main study:

Oral gavage

29 days

N/A

Final study:

29 day study:
1800: Hb (F), Hct (F), MCV (F), segm
neutrophils (F); Gluc (M), AP (M),
Creat (M)

0, 600, 1200,
or 1800
mg/kg/day

1200-1800: body weight, body weight

gain, small d-r MCH, small total
bilirubin

10 mice/sex/dose
and

600-1800: d-r deaths, temporary food

intake (M), BUN, Cl, both attributed to
renal nephrosis or dehydration, liver
weight , abs and rel weight of brain,
kidneys, heart, ovaries and testes
(possibly due to body weight)

44 mice/sex/dose
level for
toxicokinetics

Histopathology: nephrosis, thymus

atrophy
7470122
(GLP)

Weanling (5 week
old) rats
36 (control and
high dose) and
24 (low and mid
dose)/sex/group
and
10/sex/group
(for
toxicokinetics)

Oral gavage
0, 150, 300,
or 1200
mg/kg/day

26 weeks

< 150
mg/kg/
day

1200 mg/kg: body weight, body

weight gain, food intake (first week),
Urea nitrogen (M), Ca (F), inorg phosph.,
mean mandibular salivary gland weights
(possibly due to food intake), mean
prostate weight
300-1200 mg: RBC, Hb (F), Hct,
MCHC, WBC (F), LC, PTT, glucose,
albumin (M), Trigl (M), AST (F), K,
urine volume
150-1200 mg: total protein, Chol, AP,
liver and kidney weight (without
histopath correlate)
Malignant hibernomas in 6 animals
(1200 mg group: 2M + 1F at 20 weeks

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Study

Species/Sex/

ID

Number/Group

Dose/ Route

Duration

NOEL/

Major findings

NOAEL
(mg/
kg/
day)
and 2 M at 26 weeks and
150 mg group: 1M at 26 weeks)
150-300 mg/kg/day: body weight,
body weight gain

1144002
(GLP)

Weanling (4 week
old) rats,
22/sex/dose
and

Oral gavage

26 weeks

0, 30, 60, 120

or 1200
mg/kg/ day

NOAEL
120
mg/kg/
day;
NOEL
30
mg/kg/
day

18/sex/dose
(for
toxikokinetics)

1200 mg: body weight, food intake,

RBC, Hb, Hct, Ret + anisocytosis/
hyperchromia, AP, Trigl (M),
erosion/ulcer (2M + 2F) in glandular
stomach.
120-1200 mg: neutrophils, adrenal
weight without microsc correlate
60 1200 mg: Gluc, renal weight
without microsc correlate, liver weight
without microsc correlate
1000 mg: AP, basal serum ACTH.
500-1000 mg: serum cortisol response
to ACTH stimulation, aldosterone.

Dog
7470123
(GLP)

16/sex/dose (0,
1000 mg);
10/sex/dose
(250,500 mg).

Oral gavage:
0, 250, 500,
1000
mg/kg/day

52 week
with an 8week
recovery
period
Age at
start of
treatment:
68-83
days.

250-1000 mg: RBC, Hb, Ht, PLT,

Chol, Trigl, adrenal weight,
liver/gallbladder weight, spleen weight,
thyroid/ parathyroids weight ,
hepatocellular glycogen

< 250
mg/kg/
day

histopathological findings adrenals:

multifocal lymphohistiocytic infiltrates in
adrenal cortex and focal degeneration of
individual or small groups of adjacent
parenchymal cells
Terminal recovery:
1000 mg: red blood cell parameters and
PLT not fully recovered, AP not fully
recovered, adrenal weight, liver/
gallbladder weight, spleen weight,
thyroid/ parathyroid weight;
histopathological findings in adrenals not
fully recovered.
250-500 mg: histopathological findings in
adrenals not fully recovered

Genotoxicity
Ataluren genotoxicity was evaluated in vitro in gene mutation tests in bacteria and in mammalian
cells and and in vivo in rat. The studies and their results are summarised in Table 2.
Table 2

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Carcinogenicity
Carcinogenicity potential of ataluren was tested in mice and rats. In a GLP-compliant 26-week
carcinogenicity study in Tg.rasH2 mice, ataluren did not increase the incidence of tumours up to
the highest doses tested in males (600 mg/kg/day) and in females (300 mg/kg/day). The nonneoplastic findings included endometrial hyperplasia and nephropathy in females. In a GLPcompliant 24-month carcinogenicity study in rats, urinary bladder tumours (benign urothelial cell
papilloma [2 rats] and malignant urothelial cell carcinoma [1 rat]) were seen in 3/60 female rats
dosed at 300 mg/kg/day. In addition, one case of malignant hibernoma was observed in 1/60 male
rats at the dose of 300 mg/kg/day. The non-neoplastic toxicity consisted of a decrease of body
weight.
Reproduction Toxicity
The package of reproduction toxicity studies consisted of a male/female fertility study in rats,
embryo-foetal developmental toxicity studies in rats and rabbits and a peri/postnatal toxicity study
in rats. In the fertility study, no effects on male/female fertility were observed at a dose of 300
mg/kg/day, the highest dose tested, and the NOAEL for early embryonic toxicity was the same as
in the rat embryo-foetal toxicity study. In the embryo-foetal toxicity study in rat, embryo-foetal
toxicity consisted of increased early resorptions, post-implantation loss and decreased viable
foetuses and signs of developmental delay (increased skeletal variations). The NOAEL for embryofoetal toxicity was 100 mg/kg/day, giving an exposure margin of factor 4 compared to human
exposure. The NOAEL for maternal toxicity was 30 mg/kg/day.
Placental transfer of ataluren and distribution in the rat foetus was investigated with radiolabelled
ataluren. At a maternal dose of 30 mg/kg/day, the concentration of foetal radioactivity was 1/3
of the maternal concentration.
In the rabbit embryo-foetal toxicity study, maternal and embryo-foetal toxicity was seen at the
highest tested dose of 100 mg/kg/day. Embryo-foetal toxicity consisted of decreased mean foetal
weight and increased skeletal variations. At the maternal and embryo-foetal NOAEL, there was no
exposure margin compared to human exposure.
In the rat pre/postnatal developmental toxicity study, significant effects on maternal food intake
and body weight and on offspring body weight and ambulatory activity were observed at a dose of
150 mg/kg/day, i.e. at an exposure 5 times higher than the human exposure. The maternal
systemic exposure at the NOEL for neonatal toxicity was <3 and at the LOEL <4.
Toxicokinetic data
The toxicokinetics of ataluren were characterised after single and repeated daily doses of 75-1800
mg/kg/day to mice (including the mouse carcinogenicity study), 30-2000 mg/kg/day in rats
(including the rat carcinogenicity study), 25-200 mg/kg/day in pregnant rabbits (in support of
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embryo-fetal development toxicology studies) and 200-1500 mg/kg/day in dogs. The toxicokinetic
data indicated a short t and also showed that there was no significant drug accumulation in
plasma upon repeated daily dosing. Ataluren exposure increased with increasing dose, but it was
less than dose proportional at higher doses. There were no sex-related differences in ataluren
exposure in dogs, but in rats and mice, exposure was slightly higher in females than in males. The
major metabolite seen in mice, rats and dogs was ataluren acyl glucuronide.
Local Tolerance
No local tolerance studies were performed (see section 2.3.6).
Other toxicity studies
No juvenile toxicity studies were performed (see section 2.3.6).

2.3.5. Ecotoxicity/environmental risk assessment

Table 3 Summary of main study results
Substance (INN/Invented Name): ataluren
CAS-number (if available): 775304-57-9
PBT screening
Bioaccumulation potential
OECD107
log Kow
PBT-assessment
Parameter
Bioaccumulation

PBT-statement
Phase I
Calculation
PEC surfacewater , refined
(prevalence)
Other concerns (e.g. chemical
class)

Result relevant for

conclusion
log Kow

Result
4.15 at
2.19 at
0.94 at
0.41 at

pH
pH
pH
pH

3.23
5.40
7.12
8.46

Conclusion
Not PBT

Conclusion
4.15
2.19
0.94
0.41

at
at
at
at

pH
pH
pH
pH

3.23
5.40
7.12
8.46

Not PBT

Not PBT, nor vPvB

Value
0.0067

Unit
g/L

Conclusion
> 0.01 threshold
No
No

The maximal measured logKow of ataluren is 4.15 at pH 3.23) which is below the PBT screening
criterion of 4.5. A full PBT assessment has therefore not been conducted. The refined PECsurfacewater,
based on the prevalence of Duchenne muscular dystrophy (DMD) originating from nonsense
(premature stop codon) mutations (nmDMD) is calculated to be 0.0067 g/L, which is below the
threshold for progression to phase II ERA studies. It is concluded that Ataluren is not considered to
cause a potential risk to the environment.

2.3.6. Discussion on non-clinical aspects

The CHMP considered a series of studies were conducted by the applicant to characterise the
primary pharmacology of ataluren. These comprised in vitro studies in different cell model systems
including transfected human embryonic kidney, a cell-free translation system, myoblasts isolated
from mdx mice and nmDMD patients and mouse embryonic fibroblasts isolated from the IduaW392X mice. The ability of ataluren to read through premature stop codons was also investigated
in vivo using nonsense mutation mouse models of DMD, cystic fibrosis and Hurler syndrome. In the
course of the procedure, the applicant submitted results from an additional study in zebrafish to
further support the mechanism of action of ataluren. While these data suggested a plausible
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readthrough effect of ataluren on the premature stop codons under certain conditions, the CHMP
also considered recent publications, e.g. by Mc Elroy et al. 20131, which indicated a lack of
translational read-through activity for ataluren. The CHMP highlighted the conflicting nature of the
data available and the fact that the variability of results across test systems was not sufficiently
characterised. Nevertheless, it was concluded that the limited understanding of the variability in
the non-clinical setting would not be critical if sufficient clinical efficacy was shown.
The lack of readthrough of normal stop codons was supported by in vitro and in vivo studies.
Overall, the CHMP considered that the experimental data provided some reassurance that no
readthrough occurs at terminal stop codons level. Moreover, it was noted that a proteomic analysis
of HEK293 cells, treated and untreated with ataluren, will be performed by the applicant, in order
to further evaluate the potential of ataluren to promote readthrough of normal stop codons. The
CHMP recommended that these data should be submitted for review once available, as appropriate.
The bell-shaped dose response hypothesis (discussed further in the Clinical section) was supported
by data obtained from a number of in vitro test systems and in zebrafish larvae in ataluren
solution. Additional circumstantial evidence was obtained in in vivo models relevant for other
diseases. However, the CHMP considered that the bell-shaped curve was not seen in the in vivo
model of the DMD, i.e. the mdx mouse. Therefore, the applicants hypothesis that clinical efficacy
follows a bell-shaped dose-response curve was only partly supported by the non-clinical data.
Safety pharmacology studies were carried out in order to assess ataluren effects on the central
nervous system, respiratory system and cardiovascular system. No relevant effects on the CNS and
respiratory systems were observed in rats at doses up to 2000 mg/kg/day. Cardiovascular safety of
ataluren was assessed in vitro and in vivo. No relevant inhibition of ataluren on cloned hERG
channels expressed in mammalian cells was observed up to a free concentration of 100 M. The
results of in vivo studies in dogs assessing cardiovascular safety indicated that ataluren dosed up
to 1500 mg/kg did not elicit any biologically important changes in cardiovascular parameters.
The potential pharmacodynamic interactions of ataluren were explored. Of note, ataluren
readthrough effect was reduced in the presence of antibiotics known to interact with ribosomal
RNA. These studies suggested that there was no benefit to co-administration of systemic or inhaled
aminoglycoside antibiotics during treatment with ataluren and moreover, that the efficacy of
ataluren would be reduced during such co-administration.
The CHMP considered that the pharmacokinetics of ataluren were adequately characterised in the
non-clinical programme.
The applicant conducted an adequate toxicology programme for ataluren. All pivotal toxicity studies
were performed in compliance with GLP. Only the oral route of administration was investigated in
all tested species, which was considered acceptable by the CHMP.
The most important toxicity identified in mice after repeated dosing was nephrotoxicity. No NOEL
and no significant exposure margin compared to human exposure could be established. Although
this toxicity was not seen in the other species tested, i.e. rat and dog, since its mechanism in mice
is not known, the CHMP was of the view that its relevance for humans could not be ruled out.
One of the main concerns discussed was the finding of malignant hibernomas in rat. While this
finding was made only in this species, similarly to renal toxicity in mice, the CHMP concluded that
occurrence of similar effects in humans could not be excluded, particularly in the young population,
where the quantity of the brown adipose tissue is higher. In particular, the CHMP considered that
malignant hibernomas could be related to the effects of ataluren on fat tissue metabolism and to
effects on plasma lipid parameters, which were observed in rats, dogs and humans. Thus,
hibernomas were reflected in the proposed risk management plan of ataluren. The CHMP also
1

http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001593
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noted that the applicant will perform a 3 adrenergic binding assay with ataluren and one of its
metabolites to further investigate their potential effects in the brown adipose tissue in rats.
In addition to the above mentioned effects, several other less adverse effects were found in the
repeat dose studies; in particular decreased body weight gain, food intake and increased liver
weight without a histological correlate.
An adequate battery of genotoxicity tests was conducted and the data did not reveal any special
hazard for humans.
No evidence of carcinogenicity was seen in mice. In rats, cases of hibernomas were observed in the
carcinogenicity- and repeat dose toxicity studies. In addition, an increase of rare urinary bladder
tumours was found in rats, but the systemic exposure margin for these tumours compared to the
human exposure was considered sufficiently high and the finding hence of unlikely significance.
The CHMP considered that a GLP-compliant full reproductive toxicology programme consisting of
fertility and early embryonic development study, embryo/foetal development studies and a pre/postnatal development study was conducted.
The lack of formal local tolerance studies was considered acceptable by the CHMP, as ataluren is
intended for oral use and investigating the potential local gastro-intestinal effects was covered by
the oral repeated dose studies.
The CHMP considered that while no juvenile toxicity studies were performed, the repeated dose 26week rat studies started at the age of 4-5 weeks and the repeated dose 52-week dog study at the
age of 68-83 days. The CHMP was of the view that these studies were supportive of use in children
older than 4-5 years (based on the studies in rats) or slightly younger, 3-4 years (based on the
study in dogs). Overall, the CHMP concluded that the level of evidence available was, from the
perspective of non-clinical toxicity testing, sufficient to justify ataluren administration to patients 5
years and older, i.e. the patient population covered by the indication applied for.
ERA studies did not indicate potential risks to the environment linked to ataluren.

2.3.7. Conclusion on the non-clinical aspects

Overall, the CHMP concluded that despite the identified weaknesses of the pharmacology data (on
mechanism of action and bell-shaped dose-response hypothesis), the limitations within the nonclinical package could be considered acceptable, if sufficiently compensated by compelling clinical
evidence.

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2.4. Clinical aspects

2.4.1. Introduction
GCP
The Clinical trials were performed in accordance with GCP as claimed by the applicant.
The applicant has provided a statement to the effect that clinical trials conducted outside the
community were carried out in accordance with the ethical standards of Directive 2001/20/EC.
Table 4: Overview of clinical studies

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2.4.2. Pharmacokinetics
Absorption
Although ataluren is practically insoluble in water, it is readily absorbed after oral administration as
a suspension. Ataluren was rapidly absorbed with Tmax between 0.5 and 2.5 h after single doses in
fasted adult healthy volunteers. Peak plasma levels were attained approximately 1.5 hours after
dosing in subjects who received medicinal product within 30 minutes of a meal. Based on the
urinary recovery of radioactivity in a single-dose study of radiolabeled ataluren under fasting
conditions, the oral bioavailability of ataluren was estimated to be 55%.
The effect of food on ataluren bioavailability was investigated in study 001, using a formulation
(powder in bottle) different from the phase 2a/2b formulation. Based on PK modelling in healthy
volunteers and data from patients with nmDMD, no significant effect of food was detected on either
the rate or extent of ataluren absorption.
Ataluren plasma concentrations at steady state were dose-proportional for ataluren doses between
10 and 50 mg/kg. No accumulation was observed after repeated dosing.
Distribution
In vitro, ataluren was 99.6% bound to human plasma proteins and the binding was independent of
plasma concentration. Ataluren did not distribute into red blood cells.
Ataluren volume of distribution (Vz/F) varied between 393 and 689 l when single doses between 3
and 200 mg/kg were administered in healthy volunteers. A lower volume of distribution (around 50
l for a 70 kg adult) was determined in the population pharmacokinetic analysis.
Elimination
In vitro, ataluren was metabolized by conjugation via uridine diphosphate glucuronosyltransferase
(UGT) enzymes, predominantly UGT1A9 in liver and intestine. Cytochrome P450 system was not
involved in the metabolism of ataluren.
In vivo, the only metabolite detected in plasma after oral administration of radio-labelled ataluren
was the ataluren-O-1-acyl glucuronide; exposure to this metabolite in humans was approximately
8% of the plasma AUC of ataluren.
Ataluren plasma half-life ranged from 2-6 hours and was unaffected either by dose or repeated
administration. The elimination of ataluren was likely dependent on hepatic and intestinal
glucuronidation of ataluren followed by renal excretion of the resulting glucuronide metabolite.
After a single oral dose of radiolabeled ataluren, approximately half of the administered radioactive
dose was recovered in the faeces and the remainder was recovered in the urine.

In the urine,

unchanged ataluren and the acyl glucuronide metabolite accounted for <1% and 49%,
respectively, of the administered dose.
Dose proportionality and time dependencies
In study 001 conducted under fasting conditions, more than a dose proportional increase in AUC0-
of ataluren was observed over the studied dose range, i.e. 3mg/kg to 200 mg/kg. In study
PTC124-GD-002-HV under fed conditions, dose proportional increase in AUC and Cmax was seen
for ataluren between doses 10 and 50 mg/kg. After BID dosing for 7 days, plasma exposure of
ataluren increased also in a more than dose-proportional manner. In healthy volunteers, after BID
dosing of 50 mg/kg for 14 days, plasma ataluren concentrations appeared to decrease over time
with the linearity factor decreasing to 0.6, suggestive of non-linear PK at 50 mg/kg dose in this
study. Data from clinical trials on plasma concentration indicated that the steady state is
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maintained from Week 6 (the earliest measurement time) through more than two years of
treatment and based on the proposed popPK analysis it was estimated that 95% of the decrease to
the steady-state value occurs within the first two weeks of therapy.
Special populations
Age
Based on data from subjects ranging in age from 5 years to 57 years, there was no apparent effect
of age on ataluren plasma exposure.
Gender
Females were not studied in nmDMD clinical trials.

However, there were no apparent effects of

gender on ataluren plasma exposure in other populations.

Race
The pharmacokinetic properties of ataluren were not considered to be significantly affected by
UGT1A9 polymorphisms in a Caucasian population. Due to the low number of other races included
in the clinical studies, no conclusions were drawn on the effect of UGT1A9 in other ethnic groups.
Renal or hepatic impairment
No studies were conducted in patients with renal or hepatic impairment.
Non-ambulatory
There were no apparent differences in steady-state relative bioavailability and clearance due to loss
of ambulation.
Pharmacokinetic interaction studies
Effect of other drugs on ataluren pharmacokinetics
Based on in vitro studies, ataluren was a substrate of UGT1A9 and breast cancer resistant protein
(BCRP).

Caution should be exercised when ataluren is co-administered with drugs that are

inducers of UGT1A9 or inhibitors of BCRP.

Ataluren is practically insoluble in the pH range of 1.02 to 5.7, with only limited pH-dependent
solubility within this range. Since at the therapeutically recommended dose, PPIs have been shown
to increase gastric pH from average of 1.4 to median values of 3.5 to 5, no relevant interactions
with PPIs and other drugs altering gastric pH are expected.
In vitro, ataluren was not a substrate for the p-glycoprotein transporter. The pharmacokinetics of
ataluren are unlikely to be affected by medicinal products that inhibit the p-glycoprotein
transporter.
Effect of ataluren on pharmacokinetics of other drugs
In vitro, ataluren was an inhibitor of UGT1A9, organic anion transporter 1 (OAT1), organic anion
transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 (OATP1B3). Caution should
be exercised when ataluren is co-administered with drugs that are substrates of UGT1A9, OAT1,
OAT3 or OATP1B3 because of the risk of increase in concentration of these drugs.
Based on the in vitro data, ataluren is not expected to inhibit in vivo the following transporters:
BCRP, MRP2, BSEP, OATP1B1, MATE1, MATE2-K and OCT2.

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Furthermore, based on in vitro studies, ataluren was not expected to be an inhibitor of either p-gp
mediated transport or of cytochrome P450 mediated metabolism.

Similarly, ataluren is not

expected in vivo to be an inducer of cytochrome P450 isoenzymes.

Potential

interaction

between

ataluren

and

corticosteroids

was

investigated

by

analysing

pharmacokinetics in Phase 2 nmDMD patients receiving corticosteroids, and adverse events by

corticosteroid

usage

in

the

long-term

studies

in

nmDMD

patients.

Coadministration

corticosteroids with ataluren did not affect the plasma concentrations of ataluren.

of

No clinically

relevant change in the plasma concentrations of corticosteroids was seen with co-administration of
ataluren.

These data indicated no apparent drug-drug interaction between corticosteroids and

ataluren and no dose adjustments were required.

2.4.3. Pharmacodynamics
Mechanism of action
Ataluren was claimed to enable ribosomal readthrough of mRNA containing a premature stop
codon, resulting in production of a full-length protein (dystrophin). A premature stop codon within
an mRNA is a result of a nonsense mutation in DNA and causes disease by terminating translation
before a full-length protein is generated. A nonsense mutation is an underlying genetic defect in
approximately 13% of DMD patients.

Fig. 5 Mechanism of action of ataluren

Primary and Secondary pharmacology

Given atalurens mechanism of action, pharmacodynamic activity cannot be assessed in healthy
subjects

because

they

do

not

have

disease-causing

premature

stop

codons.

Therefore,

quantification of dystrophin in muscle biopsies was included as a pharmacodynamic marker in two

clinical trials of nmDMD patients.
In Study 004, muscle dystrophin expression was evaluated as the primary endpoint. This proof-ofconcept open-label study had a treatment period of 4 weeks. The extensor digitorum brevis muscle
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was sampled pre- and post-treatment to improve the ability to quantify dystrophin expression.
61% of patients showed an increase in dystrophin staining in 28 days of ataluren treatment. A
mean change from baseline to Week 4 of 11.0% in dystrophin expression was observed in the
overall study population (p=0.008, paired t-test comparing pre-treatment to post-treatment). The
mean per cent change in dystrophin expression was generally similar across the dose levels (4, 4,
8 mg/kg [n=6]; 10, 10, 20 mg/kg [n=20]; 20, 20, 40 mg/kg [n=10]) and no clear dose-response
relationship was observed, which was attributed by the Applicant to the small and unequal
numbers of patients in each group and the short duration of the study.
Muscle biopsies were also collected in the pivotal Study 007, which had a treatment period of 48
weeks. In this study, biopsy of the biceps brachii was performed from one arm at baseline (pretreatment sample) and from the other arm at Week 36 14 days (post-treatment sample) to
assess the production of dystrophin. Based on a quantitative analysis of patients with pre- and
post-treatment muscle biopsy samples, a mean change (from pre-treatment to post-treatment) of
2.8% in dystrophin expression was observed in the ataluren 10, 10, 20 mg/kg dose group, 1.3% in
the ataluren 20, 20, 40 mg/kg dose group, and 0.09% in the placebo group. These differences
were not statistically significant.
The analysis of muscle dystrophin expression in Study 007 was compromised by limitations in the
available assay methods to sensitively measure changes in dystrophin expression at low levels and
by poor sample quality in the majority of muscle biopsy samples (primarily due to artefacts
introduced in the handling and shipping of the samples). Only 19 (~11%) paired pre- and posttreatment biopsy samples met the criteria of an optimal sample, defined as no or mild freeze
artefact, good cross orientation and no more than mild or moderate fibrotic replacement. Of these
19 optimal paired samples, there were similar positive and negative changes in dystrophin
expression across all 3 treatment groups.
Other evidence of ataluren s pharmacologic action was provided from the open-label Phase 2
studies of ataluren in paediatric, adolescent and adult patients with nmCF. This disease is caused
by nonsense mutations in the gene for the cystic fibrosis transmembrane conductance regulator
(CFTR). In these studies, the activity of ataluren to restore CFTR in nmCF patients was supported
by improvements of transepithelial potential difference, which directly measures CFTR function in
the nasal mucosa.

2.4.4. Discussion on clinical pharmacology

The pharmacokinetic profile (absorption, distribution, metabolism and elimination) of ataluren was
studied in healthy volunteers and nmDMD patients and was considered sufficiently characterised in
the intended patient population.
Three formulations of ataluren were used in the programme, but no bioequivalence studies were
performed. Because of the ataluren BCS classification, the differences between the formulations in
terms of composition (excipients) were considered critical and bioequivalence could not be
established. The CHMP considered that the varying results regarding bioavailability could be
attributed to the disease status, as claimed by the MAH, but due to uncertainties in the pop-PK
modelling, this could not be confirmed.
The CHMP considered that the study 001 evaluating the effect of food was performed with Phase I
PIB formulation which could not be assumed to be bioequivalent with Phase 2a/2b formulation.
However, since clinical studies, including the pivotal Study 007 in patients with nmDMD, were
standardized regarding the food intake, i.e. Translarna was taken with food, the CHMP agreed that
the product can be recommended to be taken with food.

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The CHMP considered that the data on dose- and time linearity/non-linearity were inconclusive, but
the clinical trial data suggesting that the steady state is maintained from week 6 through more
than two years of treatment were re-assuring.
With respect to special populations, the CHMP was of the view that age-adjusted dosing would not
be required and that the data available on patients of other than Caucasian population were limited
to allow any conclusions regarding use in different ethnic groups. In the absence of specific studies
in patients with renal or hepatic impairment, the CHMP considered the pharmacokinetic properties
of ataluren. As it is extensively metabolized in liver and renal excretion accounts for 50% of the
drug elimination, hepatic and renal impairment can be expected to result in ataluren/ataluren
glucuronide accumulation. The CHMP concluded that close monitoring would be required in clinical
practice, should these patients be treated. Furthermore, additional studies addressing the
pharmacokinetics and safety in these patients were considered necessary, as described in the
proposed Risk Management Plan.
The CHMP discussed the interaction potential of ataluren and was of the view that this should be
further explored by the Applicant. Of note, as ataluren was shown to inhibit UGT1A9 in vitro, the
CHMP requested that in vivo studies with a sensitive probe substrate be conducted. Furthermore,
because of the observed time dependency, interaction study with UGT1A9 inducer should be
performed. Since ataluren may be expected to inhibit OAT1, OAT3 and OATP1B3 in vivo, in vivo
studies with sensitive probe substrates for these transporters were also deemed necessary. The
CHMP also considered that in vitro studies showed that ataluren was a substrate of BCRP and
consequently requested that the potential interactions between ataluren and a BCRP selective
inhibitor should be evaluated also in an in vivo study.
In order to characterise the mechanism of action of ataluren, a series of studies were conducted in
vitro and in vivo, as detailed in the non-clinical section. While the CHMP acknowledged that the
data from the presented studies were supportive of the readthrough ability of ataluren, recent
literature provided some evidence indicating lack of translation readthrough, rendering the
Applicants

data

less

convincing.

Furthermore,

the

CHMP

questioned

whether

the

oral

administration of ataluren in humans could lead to sufficient levels of ataluren in muscles,

considering that the available non-clinical data were based on models with intramuscular
administration or models with direct contact with ataluren solution, as was the case in zebrafish.
The CHMP considered that the most appropriate way of addressing this issue would be providing
evidence of a pharmacodynamic effect in muscles and therefore, data on dystrophin expression
from muscle biopsies were discussed by the CHMP in greater detail. Of note, the fact that data
from biopsies on dystrophin production would serve as supportive evidence was also highlighted by
the SAG Neurology experts.
In the proof-of-concept study 004, increase in dystrophin levels (mean increase of approximately
11%) was observed in about 60% of the subjects, indicating that not all subjects responded to
treatment, or at least not within 28 days. Importantly, there was no dose response relationship
and results of this study did not support the bell-shaped dose-response hypothesis of the
Applicant.
The pharmacodynamic effect suggested by the study 004 was not confirmed in the pivotal study
007. Considerable variability in the dystrophin assay was exemplified by the finding that positive
changes occurred in the placebo group, to the same extent as the ataluren treatment groups. The
CHMP considered that the lack of observed effect could be due to the poor quality of the muscle
biopsies. The GCP inspection looked into the reasons for failure to provide results from samples
obtained at the start and the end of the study and identified particularly wrong biopsy orientation
and freezing artefacts. In addition, approximately half of the biopsies exhibited moderate to severe
replacement of muscle with fat or fibrotic tissue.

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In the context of these data, the CHMP concluded that the pharmacodynamic effect of ataluren, i.e.
production of dystrophin in muscle cells of DMD patients treated with ataluren, could not be
considered confirmed. Secondly, even if dystrophin were produced in cells with advanced stage of
fibrosis, it could be questioned whether newly produced dystrophin may restore the disrupted
sarcoglycan complex which plays a role in muscle fibre stability and protection from damage.
Examples from other clinical studies with products inducing dystrophin production in muscle cells
indicated that this may not translate into convincing clinical efficacy. Overall, the lack of a
pharmacodynamic effect in study 007 was considered a weakness of the dossier and is also limiting
the external validity of the efficacy results.

2.4.5. Conclusions on clinical pharmacology

Overall, the pharmacological profile of ataluren in human studies was not adequately documented.
In particular, the CHMP concluded that there was a lack of relevant data on the pharmacodynamic
effects of ataluren in humans reinforcing the uncertainties raised on its mechanism of action and
the dose-response relationship.

2.5. Clinical efficacy

2.5.1. Dose response studies
No dose response studies were performed. Instead the preclinical data in combination with data
from the phase 2a study 004 with three doses tested (4/4/8 mg/kg, 10/10/20 mg/kg and
20/20/40 mg/kg) and a PD endpoint, were used for further determination of the dose in the
phase 2b and the extension studies.
The treatment plan in the Phase 2b study built on the Phase 2a experience in DBMD and cystic
fibrosis (CF) and on the available toxicokinetic and pharmacokinetic data from previous nonclinical and clinical studies. Because the observed ataluren pharmacodynamic activity had not
exhibited clear dose-response over the tested dose range and because the correlations between
short-term pharmacodynamic effects and long-term clinical benefit were unknown, further
exploration of dose and duration of therapy in study 007 was necessary.
The disabling and life-threatening nature of DBMD, the lack of approved therapies to treat the
underlying cause of this disease and the serious consequences of chronic corticosteroid
administration in boys with DBMD mandated that the highest tolerable dose be explored in order
to maximize the potential for benefit. Nonclinical animal data and dose-response data from the in
vitro myotube dystrophin expression experiments performed as part of the Phase 2a DMD study
(Study 004) suggested that maintaining trough ataluren plasma concentrations of >2 to 10
mcg/ml may be important to achieve optimal efficacy [Welch 2007].
The 20, 20, 40 mg/kg dosage regimen in Study 004 was associated with maximum concentration
(Cmax) and area under the concentration-time curve through 24 hours (AUC0-24) values that were
lower than and/or comparable to the mean Cmax and AUC0-24 values in nonclinical toxicity studies,
either at the 600 mg dose associated with recoverable renal lesions in mice or at the NOAEL in
rats and dogs in the 4-week toxicology studies. The mean Cmax and AUC0-24 values were also
lower than the mean values observed with the NOAEL in the 26-week rat studies and similar to
the mean values observed at the NOAEL for adrenal cortical function in the 52-week dog study.
The exposure values were also comparable to those that were generally well tolerated in adults
with CF participating in the Phase 2a study program including patients who received ataluren
treatment for 12 weeks. These exposures were generally well tolerated in boys participating in the
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Phase 2a DMD study (Study 004) for 28 days. Collectively, these considerations supported
inclusion of the 20-, 20-, 40-mg/kg dose level in the Phase 2b study.
The 10, 10, 20 mg/kg dose tested in Study 004 showed clinical pharmacodynamic activity and,
unlike the 4-, 4-, 8-mg/kg dose level, achieved trough exposure levels within the target range of
2 to 10 g/mL associated with activity in nonclinical models. The Cmax and AUC0-24 values
associated with this dose level suggested favourable exposure ratios relative to animal
toxicokinetic data. Clinically, these exposures were safe across the Phase 2a DMD and CF
experience. For these reasons, the 10, 10, 20 mg/kg dose level was also evaluated in the Phase
2b study.

2.5.2. Main study

A phase 2b efficacy and safety study of PTC124 in subjects with non-sense-mutation-mediated
Duchenne and Becker muscular dystrophy
Methods
Study Participants
To be eligible to participate in the study, patients had to be males 5 years of age who had a
diagnosis of (nonsense mutation Duchenne/Becker muscular dystrophy - nmDBMD) based on
phenotypic evidence of DBMD and a nonsense mutation in the dystrophin gene as confirmed by
gene sequencing. Patients were required to have the ability to walk 75 meters unassisted.
Adequate baseline renal, adrenal and hepatic function, as established by serum markers was
required. Key exclusion criteria included prior or ongoing clinically significant illness or severe
complications

of

DBMD,

serologic

evidence

of

hepatitis

or

and

change

in

prophylaxis/treatment for congestive heart failure within 3 months prior to start of study
treatment. Patients receiving corticosteroid therapy were required to have stabilization of such
therapy prior to study entry.
Treatments
Patients received placebo, ataluren 10, 10, 20 mg/kg (total daily dose 40 mg/kg) or ataluren 20,
20, 40 mg/kg (total daily dose 80 mg/kg) every day during the treatment period using a TID
schedule comprising morning, midday and evening doses. Approximate intervals for dosing were
to be 6 hours between morning and midday doses, 6 hours between midday and evening doses
and 12 hours between the evening dose and the morning dose on the next day.
Administration within 30 minutes after a meal was recommended. Study drug dosing was based
on milligrams of drug per kilogram of body weight. The planned duration of treatment was 48
weeks.
The use of corticosteroids was to be standardized as much as possible during the study in order to
minimize potential confounding effects. In patients not on corticosteroids at the beginning of the
study, initiation of corticosteroid therapy during the study was discouraged unless there was a
strong medical need. For patients on corticosteroids at the beginning of the study, a stable
corticosteroid regimen was to be maintained during the study. Adjustments in corticosteroid
dosage for increases in body weight were permitted but were not mandatory.
Objectives
The primary objective was to determine the effect of ataluren on ambulation.

The secondary

objectives were to evaluate the effects of ataluren on physical function, patient-reported

outcomes, cognitive function, cardiac function and pharmacodynamics. Safety, compliance with
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study drug treatment and ataluren plasma exposure were also assessed.
Outcomes/endpoints
The primary efficacy endpoint was change in 6MWD from baseline to Week 48. The secondary
endpoints comprised changes in proximal muscle function as assessed by timed function tests;
change in force exerted during knee flexion and extension, elbow flexion and extension and
shoulder abduction as assessed by myometry; change in activity in the community setting as
assessed by step activity monitoring; change in the patient-reported wheelchair use; change in
patient and parent/caregiver reported HRQL as measured by the Pediatric Quality of Life
Inventory (PedsQL); change in parent/caregiver-reported treatment satisfaction as measured by
the Treatment Satisfaction Questionnaire for Medication (TSQM); change in the rate of accidental
falls per day as recorded by patients and/or parent/caregivers in a daily diary; change in verbal
memory and attention as assessed by the digit span task; change in heart rate before, during,
and after each 6MWT as assessed by heart rate monitoring; change in serum concentration of CK;
and change in biceps muscle dystrophin expression as determined by immunofluorescence.
The safety endpoints were the type, frequency, severity, timing and relationship to study drug of
adverse

events,

laboratory

abnormalities,

vital

sign

changes,

electrocardiogram

(ECG)

abnormalities, renal ultrasound and physical exams.

The planned doses were compared to the actual doses (as reported by the patients) to determine
compliance.
Pre-dose (C0h) and 2-hour post-dose (C2h) ataluren plasma concentrations after morning drug
administration were assessed by a validated bio-analytical method.
Sample size
The hypothesis of this study was that the mean change in 6MWD from baseline to 48 weeks
would be 30 meters longer in at least one of the ataluren arms than in the placebo arm. Assuming
a common standard deviation of ~50 meters in each arm and a 1:1:1 randomization, 150
patients were required (50 patients in each of the 3 arms) to detect a difference of 30 meters in
the 6MWD with >85% power using a 2-sided Dunnett s t-test at the 0.042 significance level.
Assuming a premature discontinuation rate of ~10%, it was planned that ~165 patients (~55
patients in each of the 3 arms) be enrolled.
Randomisation
Eligible patients were randomized in a 1:1:1 ratio and stratified based on age (<9 vs 9 years),
use of corticosteroids at baseline (yes vs no) and 6MWD (350 meters vs <350 meters).
At the time of randomization, the IVR/IWR system provided the clinic pharmacist or other
qualified person with the patient randomization number and the Component ID numbers
designating the kits to be dispensed.
Blinding (masking)
Patients, parents/caregivers, investigational site personnel, PTC Therapeutics employees and all
other study personnel were to remain blinded to the identity of the treatment assignments until
every patient had completed study treatment and the database had been locked. The identity of
the study treatments were concealed by the use of a placebo that was identical to the active drug
in appearance, taste, odour, packaging, labelling and schedule of administration. Unblinding was
only to occur in the case of patient emergencies, if requested by the DMC at the time of the
interim analyses, and at the conclusion of the study. During the study, the treatment assignments
were to be available only to an independent biostatistician and to the DMC.
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Statistical methods
A mixed-model repeated-measures (MMRM) analysis of the change in 6MWD from baseline to
Week 48 was performed in the intent-to-treat (ITT) population (all randomized patients with a
valid 6MWT at baseline and 1 post-baseline visit). Included in the model were treatment,
baseline 6MWD, age (<9 or 9 years), corticosteroid use (yes or no), visit, and treatment-by-visit
interaction. Because baseline 6MWD was included in the model as a covariate, the stratification
factor of baseline 6MWD was excluded from this model. Least-squares means and variance
estimates of changes in 6MWD at Week 48 were generated from the model. These estimates were
then used to compare the changes in 6MWD at 48 weeks between each ataluren treatment arm
and the placebo arm. Normality was tested using the Shapiro-Wilks W-test at the 0.05
significance level. Because a significant degree of non-normality was observed, rank-transformed
data were used in the pre-specified analysis.
Sensitivity analyses were performed to assess the potential for induction of bias due to lack of
patient conformance to the protocol, inclusion of sibling pairs, and missing data (analysis after
multiple imputation and last observation carried forward [LOCF]) and dynamic randomization in
an MMRM setting (permutation test). A sensitivity analysis to assess robustness of the primary
efficacy results to missing data was based on the LOCF concept, by applying an analysis of
covariance (ANCOVA) model to the last available post-baseline 6MWD observation, with
covariates as defined in the SAP.
As specified in the SAP, time to persistent 10% 6MWT worsening (last time that 6MWD was not
10% worse than baseline) and time to persistent 10% 6MWT improvement (last time that 6MWD
was not 10% improved over baseline) were evaluated as supportive analyses of the primary
endpoint. Differences between each ataluren treatment arm and the placebo arm were assessed
using Kaplan-Meier methods and the stratified log-rank test.
In general, secondary variables were analysed using the final MMRM that was used for the
primary analysis of the 6MWD data, except that the baseline value of the secondary variable of
interest served as the covariate and baseline 6MWD was added to the model as an independent
variable. In cases where an MMRM analysis was not appropriate for the secondary variable of
interest, alternative statistical methods were used as necessary.
Post-hoc:
Post-hoc refined MMRM, including baseline-by-visit interaction term, analysis of 6MWD as well as
stair-climbing, stair-descending, running/walking 10 meters, and rising from supine to stand were
performed in the corrected ITT population. It was recognized after unblinding that 2 patients had
baseline 6MWTs that were incorrectly classified as valid. In fact, these 2 patients suffered from
recent lower leg injuries that reduced their baseline 6MWD when compared to their prior 6MWD at
Screening or subsequent 6MWD at Week 6. These 2 patients should not have been included in the
ITT population without a valid baseline test. To address this issue their baseline values were
replaced with screening values, creating a corrected ITT population.
Results
Participant flow
The study participant flow is shown in figure 6.
Fig. 6

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Recruitment
The study took place between 28 February 2008 (first patient first visit) and 17 December 2009
(last patient last visit).
Conduct of the study
The most common protocol deviations involved variations from protocol-specified collection times
for safety and efficacy assessments, particularly laboratory evaluations (urinalysis, haematology
and blood chemistries). Patients who did not have an evaluation that was needed for a particular
statistical analysis (e.g. missing baseline data in evaluations of change from baseline) were
excluded from that analysis. With regard to eligibility, seven of the 174 patients had laboratory
abnormalities at screening that should have excluded their participation in the study. However, a
decision had already been mad to amend the protocol to allow for inclusion of patients with
clinically insignificant laboratory abnormalities and thus, waivers were granted allowing these
patients into the study and the planned protocol amendment was subsequently implemented.
None of the patients received excluded concomitant medication and no patients were withdrawn
from the study due to developing any of the withdrawal criteria (as assessed by the adverse
event data).
Baseline data
A summary of the patient population enrolled in the study is presented in the tables below:
Table 5 Patient demographics

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Table 6 Patient disease-related characteristics

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Table 7 Patient genetic characteristics

Numbers analysed
Available data for all 57 patients who received placebo, 57 patients who received ataluren 10, 10,
20 mg/kg and 60 patients who received ataluren 20, 20, 40 mg/kg were included in analyses of
efficacy. The only patients excluded from all analyses of efficacy were those who failed screening
(see fig. 7 above).

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Outcomes and estimation

Primary outcome
The model-estimated difference (pre-specified analysis) in the mean change in 6MWD from
baseline to Week 48 between the ataluren 10, 10, 20 mg/kg and placebo arm was 26.4
meters (95% CI -4.2,57.1).

Further results of the pre-specified efficacy analysis in the ITT population, i.e. analysis of the
change in 6MWD at Week 48 is presented in table 8 below.
Table 8 Pre-specified MMRM analyses of change in 6MWD (ITT)

The observed difference between the ataluren 10, 10, 20 mg/kg and placebo arms in mean
change in observed 6MWD from baseline to Week 48 was 29.7 meters (Figure 8).
Figure 8, Mean change in observed 6MWD by Visit (ITT)

A post hoc statistical analysis was performed on the cITT population (see section Statistical
methods) and presented by the Applicant to support the efficacy of ataluren. The observed
difference in the mean change in the 6MWD from baseline to Week 48 between placebo and the
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lower dose of ataluren (10, 10, 20 mg/kg) was 31.3 metres, while the
difference was 31.7

model-estimated

(nominal p=0.0281, adjusted p=0.0561) Essentially no difference was

observed between the higher dose (20, 20, 40 mg/kg) and placebo. The results are shown in
figure 9 and table 8 below).
Fig. 9 Mean change in observed 6MWD by visit (cITT)
Change in observed 6MWD (mean SEM, m)

20
10, 10, 20 dose vs Placebo
Week 48 = +31.3 m

10
0
-10

-12.9 (sd 72) m

-20

31.3 m

-30
10, 10, 20 dose (N=57)

-40

-44.1 (sd 88) m

-50

Placebo (N=57)

-60
Baseline

12

18

24

30

36

42

48

Time (weeks)

Table. 8. Post Hoc MMRM Analysis of Change in Untransformed 6MWD based on Permutation test
(Corrected ITT).

As pre-specified, the proportions of patients with at least 10% worsening in 6MWD at Week 48
were assessed. At Week 48, 44% and 48% of patients in the placebo and 20, 20, 40 mg/kg
ataluren arms, respectively, were progressors, with no statistically significant difference between
these arms. In the 10, 10, 20 mg/kg ataluren arm, 26% of patients were progressors (nominal
p=0.0326, adjusted p=0.0652).
The hazard ratio for ataluren 10, 10, 20 mg/kg vs placebo was 0.51 representing a 49% reduction
in the risk of 10% 6MWD worsening.
Fig. 10 Time to persistent 10% 6MWD worsening (cITT)

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Secondary outcomes
Timed function tests
The results on timed function tests of muscle function (table 9) indicated positive trends for
climbing and descending four stairs and running/walking 10 metres, as evidenced by less decline
over 48 weeks; these differences were more prominent in the lower dose. No difference between
ataluren and placebo was observed for the stand to supine test.
Table 9 Timed function tests and functional method scores (cITT)

Upper and lower extremity myometry tests

Over 48 weeks, ataluren-treated patients generally showed less decline in muscle strength, as
evidenced by smaller decreases in most myometry parameters relative to placebo (table 10).
These trends were more prominent at the 10, 10, 20 mg/kg dose.
Table 10 Myometry (ITT)

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Step activity monitoring

Step activity monitoring was performed in the community setting. Patients wore a device
monitoring and recording the numbers of steps taken. Differences in changes in mean steps taken
from baseline to Week 48 favoured ataluren and placebo at both dose levels. The proportions of
time during which the patient is moving at 0 (no activity), 1-15 (low activity), 16-30 (medium
activity) and above 30 (high activity) steps/minute were also assessed (table 11).
Table 11 Proportions of time spent at no, low, medium and high activity (ITT)

Wheelchair use
Patient-reported wheelchair use showed a positive trend favouring ataluren 10, 10, 20 mg/kg vs
placebo. Mean percentage of day of wheelchair use (95%CI) increased from baseline to Week 48
by 11.5% (4.36, 18.54) for placebo, 4.0% (-2.77, 10.68) for ataluren 10, 10, 20 mg/kg and 9%
(0.7, 17.38) for ataluren 20, 20, 40 mg/kg. The treatment differences were not statistically
significant.
Frequency of accidental falls
Over 48 weeks, reductions in the frequency of accidental falls were seen at both dose levels
compared to placebo. The absolute numbers showed a decrease from baseline to Week 48 of 0.04 falls per day in the 10, 10, 20 mg/kg ataluren arm vs increase of 0.18 falls per day in the
placebo arm (table 12).
Table 12 Change in falls/day

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Treatment arm

Falls/Day (SD)
Baseline

Week 48

Placebo

0.54 (0.94)

0.72 (1.28)

Ataluren 10, 10, 20 mg/kg

0.27 (0.48)

0.23 (0.53)

Ataluren 20, 20, 40 mg/kg

0.40 (0.60)

0.28 (0.53)

Quality of life measures

Positive trends in PedsQL favoured ataluren vs placebo in the physical function domain in a prespecified analysis. The difference in the mean change in physical functioning score, favouring
ataluren 10, 10, 20 mg/kg over placebo, was 3.4 at Week 48. As with the other endpoints, this
was more pronounced in a post-hoc analysis of the decline phase subgroup; within this subgroup
a difference of 6.1 in the mean change in physical functioning score, favouring ataluren 10, 10,
20 mg/kg over placebo, was observed at Week 48.
Other secondary endpoints
Changes in the other secondary outcome measures not directly related to physical functioning
(patient-reported psychosocial functioning, treatment satisfaction, digit span task, heart rate
monitoring and serum CK) were generally small and no clear differentiation between ataluren and
placebo was observed.
Muscle dystrophin expression
The muscle dystrophin expression data were compromised by poor sample quality and
inadequacies in currently available methods for quantification of dystrophin expression.
Ataluren plasma concentration
Ataluren plasma concentration before and 2 hours following the morning dose were doseproportional and well-maintained over time. All patients who received 10, 10, 20 mg/kg ataluren
had a mean C2h across all visits less or equal to 19.3 mcg/ml. Consistent with the analysis by
treatment arm, patients who received 20, 20, 40 mg/kg ataluren but had mean C2h below or
equal to 19.3 mcg/ml showed a better response to ataluren as measured by 6MWD, timed
function tests and frequency of accidental falls than those who received the higher dose and had
C2h above 19.3 mcg/ml.
Ancillary analyses
Subgroup analyses were performed in patients who were in the decline of the disease. Criteria for
this subgroup were identified based on the results from the placebo arm which helped to define
the natural history of 6MWT in DMD (fig. 11).
Fig. 11 The natural history of DMD as defined by 6MWT data from the placebo group in study 007

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This figure shows that patients younger than 7 years tend to increase their 6MWD over 48 weeks
(maturational improvements). Patients who have higher baseline 6MWD (above 350 m) tend to
be stable over the 48-week period, whereas those patients with lower baseline 6MWD (below 350
m) show decline in their walking ability over 48 weeks.
Based on the natural history data, the applicant considered that the ability to measure a
treatment effect over a shorter period (48 weeks) would be greater in the decline-phase patients
(7-16 years, baseline 6MWD 150 metres and <80% of predicted 6MWD). This was reflected in
the design of the planned confirmatory phase 3 trial (inclusion criteria) as well as in the decline
phase subgroup analyses of the primary and secondary endpoints of study 007 (fig. 12 and fig.
13).
Figure 12 Mean change in the observed 6MWD by visit (decline phase subgroup)

Fig. 13 TFT results in the phase 2b overall population vs decline phase subgroup

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Figure 14 presents the activity of ataluren observed in patients at different ambulatory stages,
categorised based on %-predicted 6MWD at baseline, indicating a favourable effect of ataluren
across the disease spectrum, including milder patients (i.e. baseline values above 70% predicted
6MWD).
Fig. 14 Response by category of ambulatory capacity

Furthermore, evidence of a correlation between the plasma concentration achieved and the effect
in terms of 6MWT and TFTs was presented by the Applicant to support the robustness of the effect
of the selected dose (fig. 15) and a scatter plot with change in 6MWT and plasma concentration on
an individual patent level (fig. 16).
Fig. 15 Inverse concentration response in clinical data: Phase 2b study

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-20

-40

-60

Change in TFT (mean, sec)

Change in 6MWD (mean, m)

Low dose (10, 10, 20 mg/kg, N=57)

Low concentration (20, 20, 40 mg/kg, <19.3 g/mL at 2 h, N=26)
High concentration (20, 20, 40 mk/kg, >19.3 g/mL at 2h, N=33)
Placebo (N=57)

6
6MWD

Climb

Descend

10m W/R

Fig. 16 Plasma concentration versus change on 6MWT

Summary of main study

The following table summarises the efficacy results from the main study supporting the present
application. This summary should be read in conjunction with the discussion on clinical efficacy as
well as the benefit risk assessment (see later sections).
Table 13 Summary of Efficacy for trial PTC124-GD-007-DMD
Title: A Phase 2b Efficacy and Safety Study of PTC124 in Subjects with Nonsense-Mutation-Mediated
Duchenne and Becker Muscular Dystrophy
Study identifier
PTC124-GD-007-DMD
Design

Hypothesis
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multicenter, international, randomized (1:1:1), double-blind, placebocontrolled, dose-ranging study, stratified by age, corticosteroid use and
baseline 6MWD
Duration of main phase:
48 weeks
Duration of screening phase:

n.a.

Duration of extension phase:

n.a. (subject to a separate protocol)

Superiority

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Treatments groups

Placebo
Ataluren 10-10-20 mg/kg
Ataluren 20-20-40 mg/kg

Endpoints and
definitions

Primary
endpoint

6MWD

taken orally three times a day (morning,

midday, evening)
N= 57/57 (randomized/ treated)
taken orally three times a day (morning,
midday, evening)
N= 57/57 (randomized/ treated)
taken orally three times a day (morning,
midday, evening)
N= 60/59 (randomized/ treated)
Note: 1 patient was withdrawn at W6 due to
protocol non-compliance.
Change in 6-minute walk distance from
baseline to Week 48

Results and Analysis

Analysis description

Analysis population
and time point
description
Descriptive statistics

Effect estimate per

comparison

Primary Analysis A mixed-model repeated-measures (MMRM) analysis of

the change in 6MWD from baseline to Week 48 was performed in the intentto-treat (ITT) population (all randomized patients with a valid 6MWT at
baseline and 1 post-baseline visit). Included in the model were treatment,
baseline 6MWD, age (<9 or 9 years), corticosteroid use (yes or no), visit,
and treatment-by-visit interaction. Because baseline 6MWD was included in
the model as a covariate, the stratification factor of baseline 6MWD (350
or <350 meters) was excluded from this model.
Intent to treat population; time point week 48
Treatment group

Placebo

Ataluren 10-1020 mg/kg

Ataluren 20-2040 mg/kg

Number of
subjects
Baseline

57

57

60

359.5 (87.7)

350.0 (97.6)

358.2 (104.0)

Change in
observed 6MWD
Mean (SD)
Median
Min, max
The modelestimated
difference in
mean change in
untransformed
6MWD at Week
48
the modelestimated
difference in
mean change in
untransformed
6MWD at Week
48

-41.8 (89.2)
-12.9 (72.0)
-42.6 (90.1)
-36.0
-0.5
-17.0
-299.0, 172.1
-248.5, 123.1
-314.5, 127.2
Comparison groups
Ataluren 10-10-20 mg/kg
vs Placebo
Difference (meters)

26.4

95% CI

-4.2, 57.1

p-value

nominal -0.0905
adjusted 0.1592

Comparison groups
Difference (meters)

Ataluren 20-20-40 mg/kg

vs Placebo
- 0.1

95% CI

-30.4, 30.2

p-value

nominal - 0.9956
adjusted 1.0000

Clinical studies in special populations

The target patient population for the treatment with ataluren is predominantly paediatric and the
majority of subjects in the studies were children, with the exception of the phase 1 studies in
healthy volunteers. Ataluren was not evaluated in elderly patients, which is in line with the short
life expectancy of the patient population.

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No studies in patients with renal or hepatic impairment were performed (see the Clinical
pharmacology discussion, section 2.4.4).
Supportive studies
With the exception of the pivotal 007, all studies presented in the dossier were conducted as
uncontrolled:
PTC124 GD 004 DMD (as Study 004) - an open-label Phase 2a trial assessing 3 dose levels of
Translarna (4, 4, 8 mg/kg; 10, 10, 20 mg/kg; and 20, 20, 40 mg/kg) evaluating muscle
dystrophin expression as the primary endpoint.
The results of study 004 are summarised and discussed in the Clinical Pharmacology section
(2.4).
PTC124 GD 004e DMD (Study 004e) - an open-label Phase 2a extension trial assessing Translarna
20, 20, 40 mg/kg
PTC124 GD 007e DMD (study 007e) - an open label Phase 2b extension trial assessing Translarna
20, 20, 40 mg/kg
PTC124 GD 008 DMD, referred to as Study 008 - an open-label Phase 2a trial assessing
Translarna 20, 20, 40 mg/kg
After unbinding of study 007 and the observation of no separation of the high dose from placebo,
studies 004e, 007e and 008 were some prematurely stopped since patients were treated with the
20/20/40 mg/kg dose.
Two open-label studies were ongoing at the time of this marketing authorisation application:
PTC124-GD-016-DMD (Study 016) - an open-label Phase 3 safety trial of ataluren in ambulatory
and non-ambulatory patients who originally participated in Studies 007, 007e, 004, 004e or 008.
Patients were treated with ataluren 10, 10, and 20 mg/kg for an open duration.
PTC124-GD-019-DMD (Study 019) - an open-label Phase 3 safety trial of ataluren in ambulatory
and non-ambulatory patients who originally participated in Studies 007 and 007e Patients were
treated with 10, 10, and 20 mg/kg for 48 weeks.

2.5.3. Discussion on clinical efficacy

Design and conduct of clinical studies
The clinical programme of ataluren for nmDMD consisted of phase 1 single and multiple dose
studies, a phase 2a proof-of-concept study (004), one phase 2b efficacy and safety study (007)
and open label extension studies 004e and 007e. The phase 2b study was the only placebocontrolled study and was presented by the Applicant as pivotal. The CHMP considered that claims
of efficacy based on a single study could be acceptable in the context of a rare disease provided
that results of the study were sufficiently robust and compelling.
The main clinical study 007 was performed as multicentre, randomised, double-blind and placebocontrolled. The CHMP considered that the choice of placebo for the reference arm of the trial was
justified, as ataluren represents a first-in-class approach to DMD and no approved standard
therapy exists. This approach was also in line with a protocol assistance provided by the CHMP on
the product.
With respect to the choice of the inclusion and exclusion criteria, the CHMP noted that as the
distribution of age at study recruitment was wide (i.e. the age of diagnosis ranged from 0 10
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years and the age range of recruited subject ranged from 5 to 20 years) and patients with DMD
as well as BMD could be enrolled, the population was rather heterogeneous. Furthermore, as the
study included only ambulant boys, since the primary endpoint was the 6MWT, the CHMP
considered that extrapolation of efficacy results to the entire DMD patient population might be
difficult.
The applicant provided a justification as to why the 6MWT is considered the most appropriate and
relevant measurement tool for DMD and for the objectives of the study. The CHMP acknowledged
that the 6MWT is one of the most commonly applied tools for this condition and that ambulation is
a very important aspect for individuals affected by the disease. However, as discussed in
literature, the 6MWT has in itself several deficiencies, such as high inter- and intra-individual
variability. Furthermore, the results can be influenced by several factors, e.g. behaviour,
motivation, fatigue and a learning effect. Therefore, the CHMP highlighted during their follow-up
protocol assistance that clinically meaningful effects should be seen in the domains of disability
and muscle strength. Since the study was already performed with the 6MWT as the only primary
endpoint, the CHMP pointed out in this protocol assistance that the outcomes of the timed
functional tests, myometry and the other secondary endpoints should be supportive of efficacy,
i.e. pointing in the same direction.
The 48 week duration of the clinical trial was in general considered adequate to investigate the
efficacy of the test product. Still, based on the data available (and discussed below), the CHMP
noted that the ability to measure a treatment effect in 1 year was lower in patients with stable
ambulatory ability, as compared to the population of patients in the decline phase of ambulation,
which might have impacted the efficacy observed in the overall population of the study.
With respect to GCP compliance and data verification, a routine inspection and an additional
inspection requested by CHMP were performed. The inspections were conducted at the sponsor
site, two clinical investigator sites and at the central pathology laboratory where the biopsies were
analysed. The main findings pertained to archiving, AE reporting, lack of oversight (at the
investigator sites); lack of oversight and QC/QA issues (at the sponsor site) and limited GCPawareness regarding documentation and archiving (at the laboratory). With respect to the
acceptability of the clinical trial data, the inspection team considered that the data presented in
the clinical study reports were reliable and suitable for assessment in the MAA.
Efficacy data and additional analyses
The primary analysis of the data resulted in a difference of -0.1 m (95% CI -30.4, 30.2; nominal pvalue= 0.9956, adjusted p-value=1.0000) between placebo and the high dose arm and a
difference of 26.4 m (95% CI -4.2, 57.1; nominal p value=0.0905, adjusted p-value = 0.1592)
between placebo and the low dose arm. As the results were not statistically significant, the study
007 was formally considered negative. Two subjects had invalid baseline measurements; analyses
with these invalid baseline data, without these subjects or with corrected baseline values were
performed to assess the impact of different approaches. P-values varying between 0.05 and 0.09
were observed, with sometimes substantially overlapping confidence intervals in the different
analyses, but comparable results in terms of point estimates (25-35m) were seen. Taken together
with the fact that the variation in 6MWD turned out to increase over visits and exceeded the
variation accounted for in the sample size calculation, the lack of statistical significance was
assumed to be a consequence of under-powerment of the trial. Overall, the effect was considered
consistent, but the confidence intervals were too wide to be perceived as conclusive.
Further analyses and discussions were made on the corrected ITT population (cITT), which from a
methodological point of view might be considered acceptable, although the CHMP flagged the fact
that the results were post-hoc derived. In the post-hoc analysis of the primary endpoint, the
10/10/20 mg/kg group had an observed mean of 31.3 meters less deterioration on the 6MWT, as
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compared to the placebo group, while the 20/20/40 mg/kg group was not distinguishable from
placebo. The model-estimated mean showed a value of 31.7 m (95 % CI 5.1,58.3) with a nominal
p value= 0.0281 and an adjusted p value = 0.0561. The CHMP also considered the results of a
progressor analysis which was discussed during the protocol assistance and which showed that the
proportion of subjects with 10% deterioration on the 6MWT (indicating disease progression) at
week 48 was 26% in the low dose group versus 44% in the placebo and 48% in the high dose
group.
To further support the robustness of the efficacy data the applicant was requested to discuss the
outcomes on the secondary endpoints, particularly on the timed function tests and patient reported
quality of life outcomes. The results indicated trends towards better outcome on some endpoints,
e.g. 4 stair ascend, 4 stair descend, 10-m run/walk, smaller increase in time at the end of the
study was seen in the ataluren arms as compared to placebo. These differences were more
pronounced in the low dose group, but being expressed in (mili)seconds were difficult to interpret.
The frequency of patient/parent-reported accidental falling was also considered a relevant endpoint
by the CHMP, since it is related to limb fractures which further reduce the activity and may
accelerate the transition to permanent loss of ambulation. Moreover, the fact that this endpoint did
not highly correlate with the 6MWT indicated that the rate of falls is measuring a different activity
than the 6MWT. Since accidental fall rate was included in the study protocol as a secondary
endpoint, it was surprising that a rather high number of subjects had no baseline values. On
request of the CHMP the absolute figures were presented indicating that the low dose arm had
milder (on this parameter) subjects (0.27 falls/day) as compared to placebo (0.54) and high dose
arm (0.40). The absolute rates of accidental falls indicated that the population in the low dose arm
was milder in this respect. Therefore, the data on

change in accidental falls (decrease from

baseline to Week 48 of -0.04 falls per day in the 10, 10, 20 mg/kg ataluren arm, vs an increase of
0.18 falls per day in the placebo arm) were not considered as indicating a true effect of ataluren
on this parameter.
With respect to the mean percentage of wheelchair use, the CHMP considered the baseline data
and the respective increases observed in each treatment groups at week 48 and requested
additional information on the way the wheel chair use was registered. As the questionnaire did not
take into account total duration of use of a wheelchair, but only a day in which it was used, it was
considered that the variability in performance and the actual need for use of a wheelchair could not
be completely captured.
The data from the step activity monitoring indicated less increase in time spent in no activity in the
10/10/20 group, but the results were considered inconclusive. The clinical relevance of spending
2% less of the time in no activity was not substantiated.
The CHMP paid specific attention to evaluation of muscle strength, which is considered as an
important outcome for this disorder. Over 48 weeks, ataluren-treated patients generally showed
less decline in muscle strength, as evidenced by smaller decreases in most myometry parameters
relative to placebo. However, observed differences were considered to be below the level of clinical
meaningfulness. The CHMP considered the applicants argumentation that in the course of the
disease there is severe disorganisation within the muscle (at the level of muscle fibres and fibre
bundles) as well as fibrosis and aberrant innervation. Thus, in case of new production of functional
dystrophin the regeneration processes and restoration of muscle strength may indeed be time
consuming and may not be seen in a study of a shorter duration. Furthermore, as indicated by the
SAG Neurology experts, while minimal increase in dystrophin production could lead to functional
improvement, much higher levels of dystrophin in muscular fibres would have to be achieved for an
effect on strength to be seen. In this context, i.e. little supportive evidence of effect on muscle
strength, the CHMP considered that robust and convincing results on the functional outcomes

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(6MWD and functional timed tests) are of even greater importance and in the absence thereof, the
entire body of evidence of efficacy is considered weak.
Overall, the CHMP considered that the results on the secondary endpoints did not support the
primary endpoint. The view that there was little supportive evidence of effect from the data on the
secondary endpoints was also shared by the SAG Neurology experts.
In an additional post-hoc analysis of a subgroup of patients in the decline phase (older than 7
years, treated with corticosteroids, baseline 6MWD 150 metres and <80% predicted 6MWD) a
difference in mean 6MWD of -50 metres was seen, favouring ataluren 10, 10, 20 mg/kg. This result
was considered to be a clinically meaningful improvement in terms of stabilisation of walking. A
similar effect was also consistently observed in the key secondary endpoints, i.e. time function
tests, which provided reassurance to the global results. The applicant discussed this finding making
reference to the natural history data on 6MWD in DMD patients and concluded that over a shorter
period of time, subjects in the decline phase of their walking ability may show a greater effect than
patients with stabilised ambulation. At the same time, the applicant argued that in light of its
mechanism of action, i.e. production of dystrophin, ataluren should provide protection from further
damage and hence be more efficacious in less damaged muscle cells. While this would imply that
treatment should start earlier than in the decline phase, which was also supported by the SAG
Neurology experts, the CHMP maintained that the potential effect in earlier stages of the disease
was not evidenced. Overall, the CHMP considered that the patients in the decline phase of their
ambulation constituted only a subset of the study 007 population and the analysis should be seen
as exploratory. Therefore, the results to be generated in the ongoing confirmatory trial enriched
with a population of patients in the decline phase were seen as critical to addressing this issue.
The CHMP considered that even if the lack of statistical significance was disregarded, there is an
outstanding issue pertaining to the absence of effect seen in the higher dose. The applicant argued
that the finding is explained by the bell-shaped curve dose response, supporting their position by a
combination of non-clinical and clinical data. In order to further address this issue, the applicant
submitted a correlation between the plasma concentration achieved and the effect in terms of
6MWT and TFTs supporting the robustness of the effect of the selected dose (fig. 15 above). While
patients with lower concentrations appeared to show better results on 6MWD as well as across
TFTs, the CHMP considered that a scatter plot with change in 6MWT and plasma concentration on
an individual patient level would have been of greater value. This data were additionally presented
by the applicant (fig. 16 above). However, the CHMP was of the view that no specific pattern could
be identified to provide additional evidence in support of the bell shape concentration response
curve.
The data in support of the bell-shape curve hypothesis were considered to be inconsistent and not
allowing a reliable assessment. The CHMP also took into consideration the SAG Neurology comment
that additional non-clinical in vivo data would have been useful. The evidence was mainly limited to
in vitro data from myotubes derived from DMD patients and similar findings were not demonstrated
to occur in vivo. The mechanistic explanation provided by the Applicant was not considered as
sufficient level of evidence. Overall, the CHMP concluded that the effect observed in the lower dose
only could be a chance finding.
Additional expert consultation
In the course of the procedure, the CHMP identified need for input from the SAG Neurology on the
three following questions:

Question 1

Does the SAG consider that the evidence for the mechanism of action of ataluren
(nonsense mutation read-through) is convincing, and the results on dystrophin
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production could be seen as supportive of the pharmacodynamics of ataluren?

The SAG considered that mechanism of action seemed plausible, but the experts felt that the
provided data were still not convincing enough, and that they would need more information in
order to be certain. The same was true for the data provided on dystrophin production in this
case, that at least the data from the available biopsies, limited as they may be, should be
provided. Thus the SAG considered that presently the available data on dystrophin production
cannot be used as supportive of the pharmacodynamics of ataluren.

Question 2

Does the SAG agree that the presented pre-clinical and clinical evidence supports the
bell shaped dose-response curve and hence, the absence of efficacy at the higher dose
studied?
The SAG considered that the proposed hypothesis for the bell shaped dose response curve
seemed likely, but once again the experts felt that additional information was needed. More
specifically, it was noted that while evidence on the bell-shape dose-response curve was available
in several pre-clinical models, no data were generated in the mdx mouse model, relating the
production of dystrophin to the levels of ataluren in the muscle fibres. Such evidence would be
considered of relevance, as the available data describe only the relationship between plasmatic
levels of ataluren and dystrophin production.
Overall, the SAG was of the view that no clear-cut conclusions could be derived on the bellshaped dose-response hypothesis and the absence of efficacy in the higher dose studied in the Ph
II trial.

Question 3

Does the SAG consider, based on the data presented by the Applicant, that the observed
effects are sufficiently robust and clinically meaningful taking into account the results
on the primary and secondary endpoints? This should be discussed within the context
of starting treatment at all stages of the disease (as now claimed by the MAH) or in the
subgroup of patients with more advanced disease (where effects appear to be
different).
The SAG considered that although the results were not sufficiently robust, the demonstrated
effects were encouraging. The robustness of the results was challenged because of the observed
variability in the primary efficacy data, the fact that many of the important conclusions supporting
the efficacy of the drug were derived from the performed post hoc analyses, and the fact that
there was little supportive evidence of effect from the data on the secondary endpoints. At the
same time it was recognized that at the time the study was designed the knowledge of the
natural history of the disease was different from what we now know. It was agreed that the
applicant has performed the post hoc analyses in line with the most current knowledge about the
natural history of the disease, and in this respect the definition of the sub-groups in these
analyses is clinically and scientifically justified. The SAG experts considered that the results
derived from these may be considered clinically relevant, especially in the sub-group of patients
with more advanced disease. Additionally it was considered that the lack of effect on the
secondary endpoints could be explained by the expected mechanism of action of the drug i.e.
partial restoration of dystrophin production. Most of the secondary endpoints are of such nature
that any effect will have to be driven by an increase in strength, rather than an improvement of
function. The experts were presented with the latest available data, showing that minimal
increase in dystrophin production could lead to functional improvement, but not to improvement
of strength, and for the latter to occur, levels of dystrophin close to the ones in normal muscular
fibres must be achieved. The SAG experts agreed that this could be a valid explanation of the lack
of concordance between the primary and secondary endpoints efficacy data. It was also the
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position of the group that despite the fact that efficacy was most prominently shown in the subgroup of patients with more advanced disease, there were trends of efficacy in all the sub-groups
by severity, although of a different magnitude. This effect is to be expected, as according to the
data presented by the experts, the decline in function of Duchenne patients is not linear, but
rather the speed of functional decline increases with the duration of the disease. In that respect,
it would be very difficult to show a significant functional improvement in milder patients in the
frame of a controlled clinical trial with duration of 1 or 2 years. On the contrary, in the most
severe patients even a small effect on function would be detectable and clinically meaningful. The
patients and representatives in the room, in their statements, defended the position that at that
late stage of the disease even small effects providing longer independent use of arms and hands,
or preserving the ability to feed and drink from a cup on their own, would represent a significant
and important effect. Taking all of the above in consideration, the SAG experts felt that there
should be no scientific reason for the drug not to be given to milder patients if efficacy is
established in more severe ones. The long term benefit on this population could be documented
by a follow-up of data collected in specific registries.
Overall, considering the totality of the evidence available to date, the SAG was of the view that
while ataluren can be considered as a potentially efficacious drug, the data from the confirmatory
phase III trial are necessary before final conclusions on efficacy can be made.
This conclusion was shared by the CHMP.

2.5.4. Conclusions on the clinical efficacy

While the effects observed in the pivotal study were considered generally encouraging, the CHMP
considered that the clinical efficacy data submitted were not adequate and did not provide
sufficient evidence to support the indication of ataluren for the treatment of patients with
Duchenne muscular dystrophy.

2.6. Clinical safety

Patient exposure
As of 12 May 2012, a total of 588 subjects had been exposed to ataluren in completed or ongoing
clinical trials. This number comprised 76 healthy male and female volunteers, 218 male patients
with nmDMD, 270 male and female patients with nmCF and 24 male and female patients with
nmHA/HB or nmMMA (table 14).
Table 14 Patient exposure to ataluren by age group, nmDMD and other indications

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In the completed studies in patients with nmDMD, ataluren was administered three times a day at
one of three dose levels: 4, 4, 8 mg/kg; 10, 10, 20 mg/kg and 20, 20, 40 mg/kg. In the
completed studies in patients with nmCF, patients received ataluren three times a day at one of
two dose levels: 4, 4, 8 mg/kg and 10, 10, 20 mg/kg. Healthy volunteers received single doses of
ataluren up to 200 mg/kg and repeated doses up to 50 mg/kg BID for 7 days or 14 days.
Adverse events
The adverse-event profile of ataluren was comparable to that of placebo in patients with nmDMD
in the main study 007. The adverse events that were reported in 5% of patients in any
treatment arm are summarized in Table 15. The AEs which occurred twice as frequently in the
ataluren groups as compared to placebo are highlighted. None of the patients discontinued
treatment with ataluren or withdrew from the study because of a treatment-related adverse
event.
Table 15 Treatment-emergent AEs with a patient frequence of 5% by SOC (study 007)
Treatment Arm

MedDRA System Organ Class/

Preferred Terma,
Gastrointestinal disorders

Placebo

Ataluren
10, 10, 20
mg/kg

Ataluren
20, 20, 40
mg/kg

N=57

N=57

N=60

n (%)

n (%)

n (%)

37 (64.9)

42 (73.7)

44 (73.3)

Vomiting

22 (38.6)

32 (56.1)

27 (45.0)

Diarrhoea

14 (24.6)

11 (19.3)

17 (28.3)

9 (15.8)

9 (15.8)

13 (21.7)

Abdominal pain upper

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Treatment Arm
Placebo

Ataluren
10, 10, 20
mg/kg

Ataluren
20, 20, 40
mg/kg

N=57

N=57

N=60

n (%)

n (%)

n (%)

7 (12.3)

8 (14.0)

10 (16.7)

Abdominal pain

4 (7.0)

7 (12.3)

10 (16.7)

Flatulence

MedDRA System Organ Class/

Preferred Terma,
Nausea

4 (7.0)

5 (8.8)

7 (11.7)

Stomach discomfort

4 (7.0)

5 (8.3)

General disorders

21 (36.8)

23 (40.4)

20 (33.3)

Pyrexia

12 (21.1)

14 (24.6)

7 (11.7)

6 (10.5)

4 (7.0)

5 (8.3)

2 (3.5)

3 (5.3)

4 (6.7)

Infections and infestations

43 (75.4)

38 (66.7)

39 (65.0)

Nasopharyngitis

13 (22.8)

13 (22.8)

10 (16.7)

Upper respiratory tract infection

10 (17.5)

9 (15.8)

11 (18.3)

Disease progression
Asthenia

Influenza

8 (14.0)

6 (10.5)

7 (11.7)

Gastroenteritis

4 (7.0)

9 (15.8)

3 (5.0)

Rhinitis

2 (3.5)

6 (10.5)

3 (5.0)

Ear infection

3 (5.3)

3 (5.3)

4 (6.7)

Gastroenteritis viral

3 (5.3)

4 (7.0)

3 (5.0)

26 (45.6)

28 (49.1)

31 (51.7)

Fall

7 (12.3)

11 (19.3)

6 (10.0)

Procedural pain

Injury, poisoning and procedural

complications

7 (12.3)

6 (10.5)

8 (13.3)

Contusion

3 (5.3)

6 (10.5)

4 (6.7)

Joint sprain

1 (1.8)

4 (7.0)

4 (6.7)

Investigations

4 (7.0)

10 (17.5)

6 (10.0)

Weight decreased

1 (1.8)

5 (8.8)

3 (5.0)

Metabolism and nutrition disorders

3 (5.3)

7 (12.3)

6 (10.0)

Decreased appetite

2 (3.5)

5 (8.8)

5 (8.3)

19 (33.3)

25 (43.9)

28 (46.7)

6 (10.5)

7 (12.3)

8 (13.3)

Back pain

5 (8.8)

9 (15.8)

6 (10.0)

Arthralgia

2 (3.5)

2 (3.5)

6 (10.0)

Muscle spasms

5 (8.8)

3 (5.3)

1 (1.7)

Musculoskeletal and connective tissue

disorders
Pain in extremity

Muscular weakness

1 (1.8)

3 (5.3)

5 (8.3)

Nervous system disorders

17 (29.8)

25 (43.9)

18 (30.0)

Headache

14 (24.6)

22 (38.6)

15 (25.0)

Dizziness

4 (7.0)

3 (5.3)

3 (5.0)

Respiratory, thoracic and mediastinal

disorders

18 (31.6)

20 (35.1)

22 (36.7)

Cough

11 (19.3)

9 (15.8)

13 (21.7)

4 (7.0)

5 (8.8)

6 (10.0)

Nasal congestion
Oropharyngeal pain
Rhinorrhoea
Skin and subcutaneous tissue
disorders
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EMA/369266/2014

4 (7.0)

6 (10.5)

4 (6.7)

6 (10.5)

4 (7.0)

18 (31.6)

19 (33.3)

14 (23.3)

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Treatment Arm
Placebo

Ataluren
10, 10, 20
mg/kg

Ataluren
20, 20, 40
mg/kg

MedDRA System Organ Class/

Preferred Terma,

N=57

N=57

N=60

n (%)

n (%)

n (%)

Rash

5 (8.8)

4 (7.0)

8 (13.3)

Scar

3 (5.3)

4 (7.0)

5 (8.3)

The combined safety dataset for nmDMD was based on studies 007, 007e, 004e, 016 and 019.
Patients in this dataset ranged in age from 5 to 22 years and the median age was 9 years. The
combined long-term ataluren exposure was achieved in 179 nmDMD patients who received
ataluren for 48 weeks. Ataluren was generally well tolerated and the most common adverse
events (those reported in 20% of patients) included headache (40.7%), diarrhoea (27.3%),
nasopharyngitis (26.4%), cough (25.0%), upper abdominal pain (21.8%), pyrexia (21.8%), fall
(20.8%) and upper respiratory tract infection (20.8%).
Serious adverse event/deaths/other significant events
Deaths
There were no deaths during the completed clinical studies of ataluren in nmDMD patients. In the
ongoing open-label safety study for previously treated ataluren patients with nmDMD, study 016
(PTC124-GD-016-DMD), three cases of death were reported: a 22-year old male patient treated
with ataluren for ~9 months, a 21-year old male patient treated with ataluren for ~14 months
and 10-year old male patient treated with ataluren for ~18 months. Causal relationship between
the fatal outcomes and treatment with atualuren was not found.
Serious AEs
In study 007, serious adverse events were reported in 5.3% (3 of 57) subjects in the placebo
arm, in 3.5% (2 of 57) patients in the ataluren 10, 10, 20 mg/kg arm and in 3.3% (2 of 60)
patients in the ataluren 20, 20, 40 mg/kg arm.

None of the serious adverse events in either

ataluren arm was considered by the investigator to be related to ataluren (Table 16).
Table 16: Serious Adverse Events in nmDMD Placebo-controlled study 007

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There were 21 SAEs reported from studies 007,007e, 004 and 004e. Fourteen of these SAEs were
reported in patients receiving ataluren and only one (hypertension) was considered by the
applicant as likely related to the ataluren. The case of paroxysmal supraventricular tachycardia
was considered unlikely related to study drug by the applicant, because the patient had previously
experienced similar symptoms and self-limiting episodes.
There were three SAE cases of hypertension (1 in 007e and 2 in 004e) of which one was
considered as related to ataluren. In addition there were five cases of bone fractures reported
(four fractures of femur and one of lower limb) of which one occurred in the placebo arm and 4 in
patients treated with ataluren; none of these cases was considered by the investigators to be
related to ataluren.
Laboratory findings
Data obtained in healthy volunteers indicated that exposure to ataluren could cause elevation of
liver enzymes (but not bilirubin), serum cholesterol and triglycerides. These changes seemed to
be dose-dependent and reversible after exposure to ataluren was stopped.
No significant haematology findings or signals of renal toxicity and effects on adrenal function
were seen in studies 007 and 007e. The only finding was hepatic toxicity, which was expected
given the data from healthy volunteers. There were ten ataluren-treated patients and one
placebo-treated patient with isolated Grade 1 (mild) elevations in GGT or total bilirubin. Mean
cholesterol and triglycerides levels were in the upper range of normal at baseline and increased to
borderline-high or high levels in the ataluren arms and, to a lesser extent, in the placebo
treatment arm during treatment, primarily in patients who were receiving corticosteroids (Table
17).
Table 17 Mean Change in Cholesterol and Triglycerides by Treatment Arm and Corticosteroid use
in nmDMD Placebo-Controlled Study 007.

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No clear relationship was identified between pulse rate, respiration rate or temperature and the
use of ataluren, but increased blood pressure was observed (table 18). This increase was slightly
higher in the subgroup using corticosteroids than in the subgroup not using corticosteroids. There
was also a slight increase in the diastolic blood pressure in all treatment arms.
Table

18:

Mean

Change

in

Blood

Pressure

in

nmDMD

Placebo-Controlled

Study

007.

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Safety in special populations

Age-related differences in frequency of some of the frequent adverse events were observed.
Vomiting, pyrexia, abdominal pain, influenza and viral gastroenteritis were more frequent in
children aged 5 to 6 years than in older children. Headache, diarrhoea, upper abdominal pain,
nausea, falls, procedural pain, pain in extremity, back pain, rash, flatulence, disease progression,
oropharyngeal pain and dizziness occurred more frequently in the older categories.
No studies were conducted in patients with renal or hepatic impairment and safety in these populations was
not fully established. These safety concerns were proposed by the Applicant to be reflected as Missing
information in the RMP and the use of ataluren in these patients was proposed to be subject to close
monitoring.

Safety related to drug-drug interactions and other interactions

Specific drug-drug interaction studies of ataluren were not conducted. Potential interaction
between ataluren and corticosteroids was investigated by analysing pharmacokinetics in Phase 2
nmDMD patients receiving corticosteroids and adverse events by corticosteroid usage in the longterm studies in nmDMD patients. Of note, hypertension was reported in some patients
concomitantly treated with systemic corticosteroids.
In the long-term studies of ataluren in nmDMD patients (Studies 007, 007e, and 004e),
concomitant use of warfarin was not allowed because ataluren may slow the clearance of
medications that are primarily metabolized by cytochrome P450 2C9.
Safety results from the placebo-controlled study 009 in nmCF patients suggested a potential
interaction of ataluren with intravenous aminoglycosides. Serious adverse events related to renal
dysfunction, which occurred only in the ataluren arm, included three patients with acute renal
failure, three patients with renal failure and one patient with hypercreatininemia. These events
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were characterised by elevated creatinine (Grade 1 to Grade 4), which resolved over days to
weeks.

All

seven

events

were

associated

with

concomitant

systemic

treatment

with

aminoglycosides or other potentially nephrotoxic antibiotics (e.g. vancomycin) that were generally
administered as treatment for pulmonary exacerbations. No patient required dialysis. This issue
was recognized during the conduct of this study and changes were made in the protocol
(prohibition of concomitant use of intravenous aminoglycosides or other potentially nephrotoxic
antibiotics), which successfully addressed the issue.
Discontinuation due to adverse events
A total of 6 of the 216 nmDMD patients (2.8%) discontinued treatment because of one or more
adverse events. Vomiting was reported as the reason for discontinuation of treatment in two
patients. One patient discontinued due to a Grade 1 micturition disorder, indicated as unlikely
related to study drug. After the interim database cut-off date for Study 016, one additional
patient discontinued due to abnormal cystatin C and BUN values.
Discontinuation due to adverse events was also seen in the nmCF studies (e.g. due to renal and
urinary disorders).

2.6.1. Discussion on clinical safety

The safety profile of ataluren was based on data from phase 1 studies in healthy volunteers,
phase 2 studies in DMD patients and their extensions. Upon request from the CHMP during the
course of the procedure, the Applicant also provided an analysis on a combined safety data from
the nmDMD patients. Of note, more than 50% of patients were exposed to ataluren for at least
96 weeks, which was considered to constitute a sufficient long-term safety database, especially
taking into account the nature of the condition.

The CHMP also considered that additional

information on safety was derived from studies in other conditions (nmCF, nmHA/HB and
nmMMA).
With respect to data from the phase 1 studies, next to headache and gastrointestinal adverse
events, there were signals that exposure to ataluren could lead to elevation of liver enzymes as
well as serum cholesterol and triglycerides. Cases of hepatic toxicity (elevated liver enzymes)
were seen also in DMD patients in the pivotal phase 2 study 007. While these changes seemed to
be reversible after exposure to ataluren was stopped, the CHMP considered that ataluren was
intended for continuous life-long use and hence, reversibility of elevated liver enzymes was seen
as less relevant for the target population. Overall, the CHMP considered hepatotoxicity as an
important potential risk.
Similarly, the effect of ataluren on cholesterol and triglyceride levels was also documented in DMD
patients. In study 007, mean cholesterol and triglyceride levels increased to borderline-high or
high levels in both ataluren treatment arms and to a lesser extent in the placebo arm and the
increase was more prominent in patients who received corticosteroid therapy. The CHMP
considered that this would be the case in the majority of DMD patients in clinical practice and
considered this finding as a safety concern.
The treatment-related adverse events reported most commonly in the study 007 (i.e. in 5% of
patients across all 3 treatment arms) were vomiting, diarrhoea, upper abdominal pain, flatulence,
nausea, headache and decreased appetite. The CHMP considered that most of these occurred with
similar frequency in the placebo and ataluren arms. The adverse events vomiting, flatulence,
stomach discomfort and fatigue were seen to increase in frequency from placebo to ataluren 10,
10, 20 mg/kg to ataluren 20, 20, 40 mg/kg.
Increase in systolic and to a less extent in diastolic blood pressure was observed in subjects
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treated with ataluren and there were three cases of hypertension, some of which required
antihypertensive treatment. The CHMP considered that the use of corticosteroids may have
contributed to these cases. However, if authorised, ataluren would be used mostly in combination
with corticosteroids and thus, the potential risk of hypertension with concomitant use of
corticosteroids was considered as a safety concern by the CHMP, particularly in the context of a
disease with frequent development of cardiomyopathy.
Based on the combined safety dataset analysis, i.e. data from patients in studies 007, 007e,
004e, 016 and 019, the CHMP considered that ataluren was generally well tolerated by patients
with nmDMD, with the most common adverse events (those reported in 20% of patients) being
those that are typical of paediatric illnesses or DMD complications, e.g. headache (41%),
diarrhoea (27%), nasopharyngitis (26%), cough (25%), upper abdominal pain (22%), pyrexia
(22%), fall (21%) and upper respiratory tract infection (21%).
Additionally, the safety analysis indicated the changes in the lipid profile, hypertension, renal and
hepatic events need to be considered as safety concerns and reflected in the Risk Management
Plan.
The CHMP considered there were only few treatment-related serious adverse events. Femur
fracture (4.2%) was the most frequently reported serious adverse event, but none of these
fractures which met the criteria for a serious adverse event was considered by the investigators to
be related to ataluren. Although the causal relationship was not suggested by the investigators,
the CHMP paid attention to this signal, considering that lower limb fractures in DMD patients may
lead to immobilization which may become permanent, i.e. transition to non-ambulation. Further
to their review of additional data on lower limb and on all fractures both in nmDMD and in nmCF
patients, the CHMP concluded that over comparable periods, there was no signal of higher
frequency of fractures in subjects exposed to ataluren, as compared to placebo.
With respect to specific patient populations, the CHMP considered that no studies were conducted
in patients with renal or hepatic impairment and safety in these populations was not fully
established. Since renal excretion accounts for ~ 50% of the drug elimination, renal impairment is
likely to result in accumulation of ataluren and/or ataluren glucuronide. Similarly, since ataluren is
extensively metabolized in liver, hepatic impairment is expected to result in ataluren increased
plasma concentrations. Taken together with the uncertainties around the claimed bell-shaped
dose-response curve, the CHMP considered that without clinical data, understanding of both
efficacy and safety profile of ataluren in subjects with renal or hepatic impairment remains
limited.
The CHMP considered that no immunological events were reported in the DMD patients treated
with ataluren. Although immunological reactions are not expected for this type of compound, the
Applicant was requested to review all available data, including those from the CF clinical
programme. Two CF patients receiving ataluren had allergic reactions possibly related to the
investigational drug, as compared to one patient on placebo. Based on the data available,
atalurens potential for immunogenicity was considered low by the CHMP.
Despite substantial differences between the DMD and CF patient populations (differences in
demographics, concomitant medications, complications of the disease, overall health status/ need
for hospitalisations), the safety data from the combined nmCF population was considered
supportive of the safety profile for ataluren in nmDMD. Ataluren was generally well tolerated by
the nmCF patients, who were exposed to ataluren in the two long-term studies for up to two
years. The adverse events were typical of CF and included cystic fibrosis pulmonary exacerbation
(84%), cough (32%), viral upper respiratory tract infection (28%) and pyrexia (22%) as the most
frequently reported treatment-emergent adverse events (reported in 20% of patients). Most of
the adverse events were Grade 1 or Grade 2 in severity, were not attributed to ataluren and did
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not lead to discontinuation of treatment with ataluren. The data generated in the CF patients also
provided evidence of interactions between ataluren and i.v. aminoglycosides, which was
considered of relevance and supportive of a respective contraindication should the product be
authorised. Ultrasound examinations (in nmDMD and nmCF studies) identified cases of abnormal
renal ultrasound findings. In particular, the nmCF study data suggested a clear effect of ataluren
on renal abnormalities. Of note, five events of renal disorders were reported as serious adverse
events in nmCF patients. The CHMP considered that although the mechanism of a potential
contribution of ataluren to the reported cases of nephrotoxicity was not known, this signal in the
clinical development appeared to reinforce the non-clinical findings seen in mice. Based on the
clinical data available, renal toxicity was assumed to occur less likely in DMD patients, but was
still perceived as a safety concern. The CHMP concluded that it should be considered as a
potential important risk.
The CHMP pointed out a theoretical concern about possible effects of ataluren on reading through
normal stop codons and hence producing abnormally elongated proteins. This was investigated in
healthy volunteers and the results did not confirm that this would be the case. This was
considered re-assuring by the CHMP. However, these analyses were performed on a number of
selected proteins and on pooled samples from peripheral blood of healthy volunteers. Moreover,
the CHMP noted that the non-specific read through of normal stop codons should be examined in
a range of plasmatic concentrations which are expected to bring about the read-through in DMD
patients. In response to this concern, lysates from muscle biopsies obtained from 48 nmDMD
patients treated with ataluren 10, 10, 20 mg/kg for 36 weeks (Study 007) were analysed by
Western blotting. Two muscle proteins were examined (GAPDH and -actin) without further
evidence of protein elongation. Nevertheless, the CHMP was of the view that the theoretical risk
of non-specific read-through of normal stop codons still remains an uncertainty.
Furthermore, the CHMP flagged a theoretical concern that ataluren could enhance read through of
non-sense mutations in other genes. The applicant discussed the potential endogenous nonsense
codons substrates for ataluren presenting theoretical arguments why no effect on these would be
expected. However, no data were submitted in support of these statements. Overall, the CHMP
concluded that the potential off-target effects were an uncertainty about the risks related to the
mechanism of action of ataluren.

2.6.2. Conclusions on the clinical safety

Overall, the CHMP was of the view that the Applicant performed a comprehensive safety analysis
and that the safety profile of ataluren could be considered acceptable, although it was based on a
rather limited patient exposure.

2.7. Pharmacovigilance
Detailed description of the pharmacovigilance system
The CHMP considered that the Pharmacovigilance system as described by the applicant fulfils the
legislative requirements.

2.8. Risk Management Plan

The CHMP received the following PRAC Advice on the submitted Risk Management Plan:

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PRAC Advice
Based on the PRAC review of the applicants response to the previous list of questions referring
to the Risk Management Plan version 1.2, the PRAC considered by consensus that the risk
management plan for Translarna (ataluren) in the proposed treatment of Duchenne muscular
dystrophy, resulting from a nonsense mutation in the dystrophin gene (nmDMD) in ambulatory
patients aged 5 years and older, could be acceptable provided that an updated risk management
plan is submitted before final CHMP opinion, addressing the following issues:

Hepatic toxicity should be included as an important potential risk. In addition, all

corresponding sections throughout the RMP require revision accordingly.

The summary table of risk minimisation measures should be edited, as no additional risk

minimisation measures are planned for any of the safety concerns in the RMP. In the absence of
educational materials, the relevant sections of the RMP should be edited to clarify how health-care
professionals (and patients if needed) will be advised about the need for monitoring of the patients
lipid profile, renal and hepatic function monitoring and for the monitoring of blood pressure.
Genetic testing might also be considered. Furthermore, the reported risk minimisation measures in
the summary table should be limited to SmPC (i.e. no Package Leaflet references are expected).

Please note that amendments are needed in the proposed SmPC to ensure monitoring

requirements on the above mentioned issues.

Part VI of the RMP (Summary of activities in the risk management plan by product) table

VI.I.2 the objectives of the imposed PASS should be included.

This advice is based on the following content of the Risk Management Plan:

Safety concerns

Summary of safety concerns

Important identified risks
Important potential risks

Potentiation of aminoglycoside renal toxicity

Changes in lipid profile

Hypertension with concomitant use of systemic

corticosteroids

Missing information

Renal toxicity

Hibernoma

Malignancies in general

Effect of co-administration of ataluren with

nephrotoxic drugs other than intravenous

aminoglycosides

Use in patients with moderate to severe hepatic

impairment

Use in patients with moderate to severe renal

impairment

Potential use in children from 6 months to 5

years

Use in patients whose ethnic origin is other than

Caucasian

Extended long-term safety

Off-label use in patients who do not have DMD

caused by a nonsense mutation in the dystrophin gene

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EMA/369266/2014

Effect of co-administration of ataluren with

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Summary of safety concerns

certain drugs not yet evaluated in formal drug-drug
interaction studies

Pharmacovigilance plans

Activity/Study title

Objectives

(type of activity,

Safety concerns

Status Planned,

addressed

started,

Changes in lipid
profile

Planned

study title [if

known] category 13)*
Post-approval
registry(s)
Working title: LongTerm Observational
Study of Ataluren
Safety and
Effectiveness in Usual
Care

Continue to document the

long-term safety profile of
ataluren

Category 1

Evaluate the safety and

effectiveness of ataluren in
subgroups not traditionally
included in clinical trials

Obtain additional information

on
the long-term effectiveness of
ataluren

Hypertension with
use of concomitant
systemic
corticosteroids
Renal toxicity

Evaluate changes in lipid

profile
Determine the incidence and
frequency of:
o Hypertension with use of
concomitant corticosteroids
o Renal toxicity (without
concomitant aminoglycosides
or other nephrotoxic drugs)
Evaluate the safety of ataluren
in patients with moderate to
severe renal or hepatic
impairment
when used with nephrotoxic
drugs (other than
aminoglycosides)
Evaluate the safety and
effectiveness of ataluren in the
context of certain concomitant
drugs.
Monitor the
utilization pattern
of ataluren

7-day tolerability and

pharmacokinetic study
in neonatal dogs

Effect of coadministration of
ataluren with
nephrotoxic drugs
other than
intravenous
aminoglycosides
Use in patients with
moderate to severe
hepatic impairment
Use in patients with
moderate to severe
renal impairment
Potential use in
children from 6
months to 5 years
Use in patients
whose ethnic origin
is other than
Caucasian
Extended long-term
safety
Off-label use in
patients who do not
have DMD caused
by a nonsense
mutation in the
dystrophin gene
Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug
interaction studies
Potential use in
children from 6
months to 5 years

Planned

Category 3
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Activity/Study title

Objectives

(type of activity,

Safety concerns

Status Planned,

addressed

started,

Potential use in
children from 6
months to 5 years

Planned

Potential use in
children from 6
months to 5 years

Planned

Further investigation
of atalurens
potential effect in
the development of
hibernomas

Planned

Further investigation
of atalurens
potential effect in
the development of
hibernomas

Planned

Potential use in
children from 6
months to 5 years

Planned

Use in patients with

moderate to severe
hepatic impairment

Planned

Use in patients with

moderate to severe
renal impairment

Planned

Effect of
coadministration of
ataluren with certain
drugs not yet

Planned

study title [if

known] category 13)*
1-month juvenile dose
range-finding
toxicology and
toxicokinetic study
planned in neonatal
dogs (age correlating
with dosing in newborn
paediatric patients to 2
years of age), Study 2
of
EMA/PDCO/476743/20
12 PDCO document.
Category 3
3-month juvenile
toxicology and
toxicokinetic study
planned in neonatal
dogs (age correlating
with dosing in newborn
paediatric patients to 2
years of age), Study 3
of
EMA/PDCO/476743/20
12 PDCO document
Category 3
3 adrenergic binding
assay with ataluren
and the M4 metabolite,
if such a study is
technically feasible
Category 3
Plan to investigate
further
postauthorisation the
potential effects of
ataluren and
metabolite M4 in
brown adipose tissue
of rats.
Category 3
Open-label safety and
PK study in children
age 6 months to 5
years, Study 6 of
EMA/PDCO/476743/20
12 PDCO document
Category 3
Safety and PK study in
patients with moderate
to severe hepatic
impairment
Category 3

Safety and PK study in

patients with moderate
to severe renal
impairment
Category 3

Safety and PK study of

co-administration of
ataluren and a
sensitive probe for
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EMA/369266/2014

To evaluate the safety and PK

of ataluren in subjects with
different degrees of hepatic
impairment, in order to provide
guidance for ataluren dosing in
patients with moderate to
severe hepatic impairment.
To evaluate the safety and PK
of ataluren in subjects with
different degrees of renal
impairment, in order to provide
guidance for ataluren dosing in
patients with moderate to
severe renal impairment.
To evaluate the safety and PK
of ataluren and/or the
appropriate sensitive probe
substrate, in order to provide

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Activity/Study title

Objectives

(type of activity,

Safety concerns

Status Planned,

addressed

started,

study title [if

known] category 13)*
induction of UGT1A9
Category 3
Safety and PK study of
co-administration of
ataluren and a
sensitive probe for
substrates of UGT1A9
Category 3
Safety and PK study of
co-administration of
ataluren and a
sensitive probe for
inhibitors of the
transporter breast
cancer resistant
protein (BCRP)
Category 3
Safety and PK study of
co-administration of
ataluren and a
sensitive probe
substrate of organic
anion transporter 1
(OAT1)
Category 3
Safety and PK study of
co-administration of
ataluren and a
sensitive probe
substrate for organic
anion transporter 3
(OAT3)
Category 3
Safety and PK study of
co-administration of
ataluren and and a
sensitive probe
substrate organic
anion transporting
polypeptide 1B3
(OATP1B3)
Category 3

guidance for dosing ataluren

with the specific concomitant
medication.
To evaluate the safety and PK
of ataluren and/or the
appropriate sensitive probe
substrate, in order to provide
guidance for dosing ataluren
with the specific concomitant
medication.
To evaluate the safety and PK
of ataluren and/or the
appropriate sensitive probe
substrate, in order to provide
guidance for dosing ataluren
with the specific concomitant
medication.

evaluated in formal
drug-drug
interaction studies
Effect of
coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug
interaction studies
Effect of
coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug
interaction studies

To evaluate the safety and PK

of ataluren and/or the
appropriate sensitive probe
substrate, in order to provide
guidance for dosing ataluren
with the specific concomitant
medication.

Effect of
coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug
interaction studies

Planned

To evaluate the safety and PK

of ataluren and/or the
appropriate sensitive probe
substrate, in order to provide
guidance for dosing ataluren
with the specific concomitant
medication.

Effect of
coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug
interaction studies

Planned

To evaluate the safety and PK

of ataluren and/or the
appropriate sensitive probe
substrate, in order to provide
guidance for dosing ataluren
with the specific concomitant
medication.

Effect of
coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug
interaction studies

Planned

Planned

Planned

Risk minimisation measures

Safety concern

Routine risk minimisation measures

Additional risk
minimisation
measures

Potentiation of aminoglycoside

SmPC section 4.3 (Contraindications)

renal toxicity

Concomitant use of intravenous

None proposed

aminoglycosides (see section 4.5).

SmPC section 4.5 (Interaction with other
medicinal products and other forms of
interaction)
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Safety concern

Routine risk minimisation measures

Additional risk
minimisation
measures

Aminoglycosides
Translarna should not be co-administered
with intravenous aminoglycosides, based on
cases of decreased renal function observed in
a clinical trial in patients with nonsense
mutation cystic fibrosis (nmCF) (see section
4.3).
Elevations of serum creatinine occurred in
several nmCF patients treated with Translarna
and intravenous aminoglycosides together
with other antibiotics for cystic fibrosis
exacerbations. The serum creatinine
elevations resolved in all cases, with
discontinuation of the intravenous
aminoglycoside, and either continuation or
interruption of the study drug. These findings
suggested that co-administration of
Translarna and intravenous aminoglycosides
may potentiate the nephrotoxic effect of the
aminoglycosides. Treatment with Translarna
can be resumed 2 days after administration of
the aminoglycoside has ended. The effect of
co-administration of ataluren with other
nephrotoxic drugs is unknown.
Dehydration may be a contributing factor in
some of these cases. Patients should maintain
adequate hydration while taking Translarna.
PIL section 2
(What you need to know before you take
Translarna)
Do not take Translarna if you are taking
injection by vein for antibiotics, such as
gentamicin, tobramycin, or streptomycin.
(Other medicines and Translarna)
Tell your doctor if you are taking, have
recently taken, or might take any other
medicines. In particular do not take
Translarna with gentamicin, tobramycin, or
streptomycin injections.
These may affect your kidney function.
Changes in lipid profile

SmPC section 4.8 (Undesirable effects)

Monitoring of the

Change in lipid profile (increased triglycerides

patients lipid profile

and cholesterol) are included in Table 1.

on an annual basis.

(Description of selected adverse

reactions)
Serum lipids

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Safety concern

Routine risk minimisation measures

Additional risk
minimisation
measures

During the controlled study of nmDMD, mean

total cholesterol and triglycerides were in the
upper range of normal at baseline and
increased, reaching borderline high or high
values. The values tended to stabilize early in
the study and did not increase further with
continued treatment.
Hypertension with concomitant use

SmPC section 4.8 (Undesirable effects)

Monitoring of resting

of corticosteroids

Hypertension is included in Table 1

systolic and diastolic

blood pressure every
6 months, or more
frequently as needed
based on the patients
clinical status.

Renal toxicity

SmPC section 4.8 (Undesirable effects)

Monitoring of the

Change in renal function tests (increased

renal laboratory tests

creatinine, BUN, cystatin C) are included in

(serum creatinine,

Table 1.

BUN, cystatin C)
every 6 to 12 months.

(Description of selected adverse

reactions)
Renal function tests
During the controlled study of nmDMD, small
increases in mean serum creatinine, blood
urea nitrogen (BUN), and cystatin C were
observed. The values tended to stabilize early
in the study and did not increase further with
continued treatment.
Hibernoma

PIL Section 4 (Possible side effects)

None proposed

Reporting of side effects

If you have any side effects, talk to your
doctor or pharmacist. This includes any
possible side effects not listed in this leaflet.
You can also report side effects directly via
the national reporting system listed in
Appendix V. By reporting side effects you can
help provide more information on the safety
of this medicine.
Malignancies in general

PIL Section 4 (Possible side effects)

None proposed

Reporting of side effects

If you have any side effects, talk to your
doctor or pharmacist. This includes any
possible side effects not listed in this leaflet.
You can also report side effects directly via
the national reporting system listed in
Appendix V. By reporting side effects you can
help provide more information on the safety

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Safety concern

Routine risk minimisation measures

Additional risk
minimisation
measures

of this medicine.
Use of ataluren in nmDMD patients

SmPC section 4.5 (Interaction with other

who co-administered ataluren with

medicinal products and other forms of

nephrotoxic drugs

interaction)

None proposed

The effect of co-administration of ataluren

with other nephrotoxic medicinal products is
unknown.
PIL section 2 (other medicines and
translarna) Tell your doctor if you are
taking, have recently taken, or might take
any other medications.
Use of ataluren in nmDMD patients

SmPC section 4.2 (Posology and method

with moderate to severe hepatic

of administration)

impairment

Renal and hepatic impairment

None proposed

Safety and efficacy of ataluren in patients

with renal and hepatic impairment have not
been established.
SmPC section 4.4 (Special warnings and
precautions for use)
Patients with renal and hepatic impairments
should be closely monitored.
SmPC section 5.2 (Pharmacokinetic
properties)
Renal or hepatic impairment
No studies have been conducted with
Translarna in patients with renal or hepatic
impairment. Patients with renal or hepatic
impairment should be monitored closely.
PIL section 2. (What you need to know
before you take Translarna)
Warnings and precautions If you have any
liver or kidney problem, your doctor should
check your liver and kidney functions
regularly.
Use of ataluren in nmDMD patients

SmPC section 4.2 (Posology and method

with moderate to severe renal

of administration)

impairment

Renal and hepatic impairment

None proposed

Safety and efficacy of ataluren in patients

with renal and hepatic impairment have not
been established.
SmPC section 4.4 (Special warnings and
precautions for use)

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Safety concern

Routine risk minimisation measures

Additional risk
minimisation
measures

Patients with renal and hepatic impairments

should be closely monitored.
SmPC section 5.2 (Pharmacokinetic
properties)
Renal or hepatic impairment
No studies have been conducted with
Translarna in patients with renal or hepatic
impairment. Patients with renal or hepatic
impairment should be monitored closely.
PIL section 2. (What you need to know
before you take Translarna)
Warnings and precautions If you have any
liver or kidney problem, your doctor should
check your liver and kidney functions
regularly.
Potential use in children from 6

SmPC section 4.1 (Therapeutic

months to 5 years old

indications)

None proposed

Translarna is indicated for the treatment of

Duchenne muscular dystrophy resulting from
a nonsense mutation in the dystrophin gene,
in ambulatory patients aged 5 years and
older. Efficacy has not been demonstrated in
non-ambulatory patients.
SmPC section 4.2 (Posology and method
of administration)
The safety and efficacy of Translarna in
children and infants less than 5 years old
have not yet been established.
PIL Section 1 (What Translarna is and
what it is used for)
Children and adolescents
This medicine has not been tested in children
under 5 years.
Use of ataluren in patients whose

SmPC section 5.2 (Pharmacokinetic

ethnic origin is other than

properties)

Caucasian

It is unlikely that the pharmacokinetics of

None proposed

ataluren are significantly affected by UTG1A9

polymorphisms in a Caucasian population.
Due to the low number of other races
included in the clinical studies, no conclusions
can be drawn on the effect of UTG1A9 in
other ethnic groups.
Extended long-term

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None proposed

None proposed

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Safety concern

Routine risk minimisation measures

Additional risk
minimisation
measures

Safety
Off-label use of ataluren in patients

SmPC section 1 (Therapeutic indications)

Central certification of

who do not have DMD

The presence of a nonsence mutation in the

nonsense mutation in

caused by a nonsense mutation in

dystrophin gene should be determined by

the dystrophin gene

the dystrophin gene

genetic testing.

required for
prescription to be

PILsection 2 (Warnings and precautions)

filled.

Your doctor must have results of a blood test

to confirm that Translarna may be helpful in
treating your abnormal muscle function.
Effect of coadministration of

SmPC section 4.4 (Special warnings and

ataluren with certain drugs not yet

precautions for use)

evaluated in formal drug-drug

Caution should be exercised when ataluren is

interaction studies

co-administered with medicinal products that

None proposed

are substrates or inducers of UGT1A9,

inhibitors of BCRP, or substrates of OAT1,
OAT3, or OATP1B3.
SmPC section 4.5 (Interaction with other
medicinal products and other forms of
interaction)
Based on in vitro studies, ataluren is an
inhibitor of UGT1A9, organic anion
transporter 1 (OAT1), organic anion
transporter 3 (OAT3) and organic anion
transporting polypeptide 1B3 (OATP1B3).
Caution should be exercised when ataluren is
coadministered with drugs that are substrates
of UGT1A9, OAT1, OAT3, or OATP1B3
Information in PIL 2 (What you need to
know before you take Translarna)
Tell your doctor if you are taking any of the
following medicines: propofol, mycophenolate
mofetil, phenobarbital, rifampin, cyclosporine,
eltrombopag, gefitinib, adefovir, captopril,
furosemide, lamivudine, methotrexate,
oseltamivir, tenofovir, zalcitabine, zidovudine,
acyclovir, bumetanide, ciprofloxacin,
famotidine, penicillin G, sitagliptin,
pravastatin, rosuvastatin, atorvastatin,
pitavastatin, telmisartan, valsartan, or
olmesartan. These medicines were not tested
together with Translarna and your doctor may
decide to monitor you closely.

The CHMP, having considered the data submitted in the application was of the opinion that it was
not appropriate to consider pharmacovigilance activities and risk minimisation measures at this
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time.

2.9. User consultation

The results of the user consultation with target patient groups on the package leaflet submitted
by the applicant show that the package leaflet meets the criteria for readability as set out in the
Guideline on the readability of the label and package leaflet of medicinal products for human use.

3. Benefit-Risk Balance
Benefits
Beneficial effects
Ataluren is a first-in-class drug designed to enable ribosomal readthrough of premature stop
codons, resulting in the formation of a full-length functional protein in patients with nonsense
mutation genetic disorders. In the proof of concept study in mdx mice ataluren was seen to
promote formation and adequate localization of dystrophin, resulting in increased muscle strength
and prevention of loss of strength following repeated contractions.
In the clinical setting, beneficial effects of the lower dose (10, 10, 20 mg/kg) were claimed in
both primary and secondary endpoints of physical functioning.
With respect to 6MWD, ataluren was observed to slow disease progression in nmDMD patients.
The post-hoc analysis in the cITT population indicated an estimated difference in the Change in
6MWD at Week 48 of 31.7 metres (nominal p=0.0281, adjusted p=0.0561, observed mean
difference in 6MWD=31.3 metres) between the 10, 10, 20 mg/kg dose and placebo. Looking at
the proportions of patients with at least 10% worsening in 6MWD at Week 48, 44% vs 26% of
patients in the placebo and the 10, 10, 20 mg/kg ataluren arm, respectively were progressors
(nominal p=0.0326, adjusted p=0.0652) .
A greater effect over 48 weeks was seen in patients in the ambulatory decline phase, i.e.
patients between 7 and 16 years of age, with baseline 6MWD 150m and 80% of predicted
value. Based on a post-hoc subgroup analysis in this population, a difference in the change in
6MWD at Week 48 of 49.9 metres (p=0.0096) between the 10, 10, 20 mg/kg dose and placebo
was seen.
In terms of secondary endpoints of physical functioning, only limited effects of ataluren were
observed: ataluren patients had fewer falls/week than placebo-dosed patients; increase of
wheelchair use from baseline was less in ataluren than placebo; ataluren patients spent less time
in no activity (based on Step activity monitoring) and a minor positive trend was observed in
myometry tests.
Uncertainty in the knowledge about the beneficial effects
The CHMP was of the view that the main uncertainties about the claimed beneficial effects
pertained to the robustness of efficacy data in general, the dose-response curve (and hence the
appropriate dose) and the applicability of the data to the overall target population.
Uncertainties about robustness of efficacy data
The primary analysis of the pivotal study 007 indicated an estimated difference of 26.4 m
between placebo and the low dose arm; this, however, was not statistically significant (nominal
p=value 0.0905, adjusted p value=0.1592) and by the usual statistical standards, the study was
formally negative. In order to explain the findings in study 007, the Applicant performed a
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number of post hoc analyses. These consistently showed a similar difference in 6MWD, but the
wide confidence intervals reflected the uncertainty in the estimate.
The CHMP was of the view that the results on the secondary endpoints provided only limited
support for the primary endpoint outcomes, as they were inconsistent, difficult to interpret and
needed to be seen only as trends. Nevertheless, in line with the input from the SAG Neurology,
the CHMP acknowledged that most of the secondary endpoints were of such nature that any effect
would have to be driven by an increase in strength and for this to occur, higher levels of
dystrophin in muscular fibres would have to be achieved.
Pharmacodynamic confirmation of efficacy was not provided by the pivotal study, despite the fact
that biopsies were collected. While the technical problems with dystrophin quantification were
recognised by the CHMP, the quality of the biopsies supplied was of concern. The GCP inspection
identified that several steps were underestimated, namely instructions for performing the muscle
biopsies and the storage/ shipping logistics. Since the mechanism of action of ataluren is claimed
to be by promoting production of a full-length dystrophin, more prominent evidence of dystrophin
in muscle of patients treated for 48 weeks would be expected. Considering the limitations of data
on clinical efficacy, the CHMP pointed out that the dossier would have benefited from supportive
data on pharmacodynamics and their absence was seen as adding to the uncertainties.
Uncertainties about the dose-response curve and dose
The CHMP considered that one of the critical issues was the absence of effect in patients treated
with the higher dose. The applicant argued that the finding could be explained by the bell-shaped
curve dose response, supporting their position by a combination of in vitro data (e.g. human
myotube cultures, nmDMD mouse myotubes and nmDMD zebrafish) and clinical data (studies
004e, 007 and 007e). The bell-shape response curve was however not obvious based on the in
vivo preclinical data and the phase 2a clinical data, i.e. before the design and start of the clinical
studies 004e, 007 and 007e.
In order to further address this issue, the applicant submitted a correlation between the plasma
concentration achieved and the effect in terms of 6MWT and TFTs supporting the robustness of the
effect of the selected dose. While patients with lower concentrations appeared to show better
results on 6MWD as well as across timed function tests, the CHMP considered that a scatter plot
with change in 6MWT and plasma concentration on an individual patient level would have been of
greater value. This data were additionally presented by the applicant, but no specific pattern could
be identified to provide additional evidence in support of the bell shape concentration response
curve.
Overall, the data in support of the bell-shape curve hypothesis were considered to be inconsistent
and not allowing a reliable assessment. The CHMP concluded that the effect observed in the lower
dose only could be a chance finding.
Validity of data for the entire nmDMD patient population
Since efficacy was investigated in a subgroup of ambulant DMD boys and documented mainly on
ambulation parameters, extrapolation to the broader nmDMD patient population (including nonambulant subjects) was not supported by sufficient evidence.
Risks
Unfavourable effects
Ataluren was generally well tolerated by patients with nmDMD, with the most common adverse
events being headache and gastrointestinal disorders such as nausea, vomiting, (upper)
abdominal pain, flatulence, diarrhoea, stomach discomfort, constipation and regurgitation.
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The laboratory data indicated that exposure to ataluren could cause elevation of serum
cholesterol and triglycerides. Mean cholesterol and triglycerides levels were in the upper range of
normal at baseline and increased to borderline-high or high levels in the ataluren arms, primarily
in patients who were receiving corticosteroids. The values tended to stabilize early and did not
increase further with continued treatment. Changes in the lipid profile were considered as an
important identified risk in the proposed Risk Management Plan.
Of note, elevations of serum creatinine occurred in several patients with nonsense mutation cystic
fibrosis treated concomitantly with intravenous aminoglycosides. In all cases, the elevations
resolved with discontinuation of the aminoglycosides indicating that co-administration of ataluren
and intravenous aminoglycosides may potentiate the nephrotoxic effect of the aminoglycosides.
Based on this evidence of decreased renal function, potentiation of aminoglycoside renal toxicity
was determined as an important identified risk.
There were no deaths during the placebo controlled study. Three fatal cases were seen in one
open-label study, but the fatal outcomes were not considered related to treatment with ataluren.
Uncertainty in the knowledge about the unfavourable effects
From the non-clinical database, the finding of malignant hibernomas in rat raised the concern as
to whether occurrence of similar effects could be expected in humans, particularly in the
paediatric population where the quantity of the brown adipose tissue is higher. In particular, the
CHMP considered that malignant hibernomas could be related to the effects of ataluren on fat
tissue metabolism and to effects on plasma lipid parameters, which were observed in rats, dogs
and humans. Thus, hibernomas were reflected in the proposed risk management plan of
ataluren as an important potential risk.
Considering the mechanism of action of ataluren, the CHMP pointed out a theoretical concern
about possible effects of ataluren on reading through normal stop codons (and thus producing
abnormally elongated proteins) and a concern that ataluren could enhance read through of nonsense mutations in other genes. Although such effects were not seen in the data available, the
CHMP was of the view that the potential off-target effects were an uncertainty about the risks of
ataluren.
Based on results of in vitro studies, ataluren was expected to have an interaction potential, which
the CHMP considered necessary to be explored further in vivo. This pertained to ataluren
interactions with a BCRP inhibitor, UGT1A9 substrate, OAT1, OAT3 and OATP1B3 substrates and
UGT1A9 selective inducer.
Increase in blood pressure including cases of hypertension requiring antihypertensive treatment
was observed in subjects treated with ataluren. While this could have been due to the use of
corticosteroids administered concomitantly, this issue was considered an uncertainty and captured
as a potential risk in the proposed Risk Management Plan.
The preclinical data as well as data from healthy volunteers and DMD patients indicated that
exposure to ataluren may lead to increase in transaminases. While these changes seemed to be
reversible after exposure to ataluren was stopped and a clear hepatotoxic effect was not
confirmed, the CHMP considered hepatotoxicity as an important potential risk.
The nmCF study data suggested an effect of ataluren on renal abnormalities. Although the
mechanism of a potential contribution of ataluren to the reported cases of nephrotoxicity was not
known, this signal in the clinical development appeared to reinforce the non-clinical findings seen
in mice. Based on the clinical data available, renal toxicity was assumed to occur less likely in
DMD patients, but was still perceived as a potential important risk.
Treatment of patients with renal or hepatic impairment is another area of uncertainty, as no
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specific

studies

were

performed

and

potential

safety

concerns

are

implied

by

the

pharmacokinetics of ataluren. Since renal excretion accounts for ~ 50% of the drug elimination,
renal impairment is likely to result in accumulation of ataluren and/or ataluren glucuronide.
Similarly, since ataluren is extensively metabolized in liver, hepatic impairment is expected to
result in ataluren increased plasma concentrations. Taken together with the uncertainties around
the claimed bell-shaped dose-response curve, the CHMP considered that without clinical data,
understanding of both efficacy and safety profile of ataluren in subjects with renal or hepatic
impairment remains limited.
Benefit-risk balance
Importance of favourable and unfavourable effects
Several lines of evidence support the clinical relevance of a 30-meter difference in 6MWT,
including a report2 showing that a 30-meter change in 6MWD over 48 weeks can be considered a
clinically meaningful change based on the patient/parent-reported quality of life measures in DMD
patients. This is also supported by results of longitudinal LMWT natural history data in DMD,
indicating that each 30-meter decrease in baseline 6MWD predicts increasing risk of loss of
ambulation over the following 2 years.
Ability to climb and descend a short grouping of stairs, abililty to run in short bursts, or to walk a
short distance unaided, e.g. to a bathroom, reflect the typical activities important in the lives of
DMD patients. Importantly, recent data indicated that timed function tests evaluating these
abilities are, similarly to 6MWT, predictive of the time for a patient to become non-ambulatory.
Natural history data from the Cooperative International Neuromuscular Group indicated that
changes in these parameters are predictive of the likelihood of loss of ambulation over 1 year.
Falls commonly lead to fractures in DMD patients and the injuries sustained may accelerate loss
of ambulation. Decreasing the rate of accidental falls and hence the risk of fractures, pain and
other trauma would be of benefit to the patients. With respect to decrease in wheel chair use,
benefits can be attributed not only in terms of ambulation itself, but also by positively impacting
on the respiratory function and minimalisation of scoliosis. Thus, if sufficiently documented these
effects would be considered of high importance.
The most commonly reported treatment-related adverse events vomiting, diarrhoea, abdominal
pain upper, flatulence, nausea, headache and decreased appetite were not considered to raise
major safety concerns in a seriously debilitating and life-threatening condition such as DMD.
The effect of ataluren on the lipid profile (cholesterol and triglyceride levels) was considered of
importance, especially in a situation where long-term administration of corticosteroids is
expected. Nevertheless, the values tended to stabilize early in the study and did not increase
further with continued treatment, which was considered re-assuring. Similarly, the risk of
hypertension during concomitant use of corticosteroids and ataluren was seen as of importance to
the target population, considering that such co-administration would occur in the majority of
patients in the clinical practice.
In the context of the age group targeted, the potential risk of hibernoma was considered relevant,
due to higher proportion of brown fat tissue in children.

Henricson E, Abresch R, Han JJ, Nicorici A, Goude Keller E, de Bie E, McDonald CM. The 6-Minute Walk Test and
Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal
Comparisons and Clinically-Meaningful Changes Over One Year. PLOS Currents Muscular Dystrophy. 2013 Jul 8;
5:ecurrents.md.9e17658b007eb79fcd6f723089f79e06. doi:
10.1371/currents.md.9e17658b007eb79fcd6f723089f79e06
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Discussion on the benefit-risk balance

The CHMP considered that the data presented in the dossier had several deficiencies which
impacted on the benefit-risk assessment. In particular, the Applicant conducted only a single
pivotal trial and with the formal failure of its primary analysis, the efficacy discussion was based on
post hoc analyses. It was agreed that these analyses were performed in line with the most current
knowledge about the natural history of the disease (gained during the conduct of study 007), and
in this respect the definition of the subgroups in these analyses was clinically and scientifically
justified (e.g. patients in decline phase of their ambulation). While the effects observed in the
pivotal study were considered generally encouraging, as supported also by the SAG Neurology, the
CHMP was of the view that they still need to be seen as failing to provide compelling evidence of
efficacy (due to the failure of the primary analysis).
Considering the limitations of data on clinical efficacy, the CHMP pointed out that the dossier would
have benefited from supportive data on pharmacodynamics, i.e. data on dystrophin production in
human muscle and evidence supporting the bell-shape dose response hypothesis. In this respect,
the CHMP noted that while dystrophin production was observed in the phase IIa study 004, the
limited data from the pivotal study (due to the low quality of muscle biopsies) precluded
confirmation of a pharmacodynamic effect. Even though it was acknowledged that dystrophin is not
a valid biomarker for efficacy, the mechanism of action is directly linked to its production and the
limited data from study 007 on dystrophin production contributed to the overall uncertainties.
As discussed above, the bell-shape dose response hypothesis was used by the Applicant to explain
why effects were only seen with the lower dose (10, 10, 20 mg/kg). The CHMP considered that
unless the hypothesis is supported by sufficient (non)-clinical data, the observation of an effect in
the lower dose and no effect in higher dose could be considered as a chance finding. Taking into
account all available evidence, the CHMP was of the view that the bell-shaped dose response
hypothesis was not confirmed.
Furthermore, the CHMP was of the view that the results on the secondary endpoints provided only
limited support for the primary endpoint outcomes, as they were inconsistent, difficult to interpret
and could be considered only as trends. In particular, the fact that endpoints more directly linked
to the daily living activities or those reflecting the negative impact of the condition (falls, level of
physical activity or wheelchair use) did not show a re-assuring effect was of concern.
All these aspects taken together were considered as having a negative impact on the robustness of
the data in a broader sense, i.e. in addition to the statistical considerations.
In their discussion, the CHMP also focused on the fact that ataluren was evaluated only in
ambulatory patients, whereas the product was intended for a broader patient population.
Furthermore, considering that the beneficial effects were most prominent in a sub-population of
ambulatory patients in the decline phase of their walking ability (effect size of approximately 50
metres on the 6MWD), the CHMP discussed whether the benefit-risk balance could be considered
favourable in this population, and whether this should lead to a restriction of the proposed
indication. Of note, the SAG experts felt that scientifically there should be no reason for the drug
not to be given to milder patients if efficacy had been established in more severe ones. This was
considered by the CHMP, but the overall conclusion was that based on the level of uncertainties,
efficacy could not be reliably established even in this subpopulation.
Although the safety data identified some safety concerns, in general these were considered
manageable through the implementation of adequate pharmacovigilance activities and risk
minimisation measures as described in the proposed Risk Management Plan. The lack of serious
toxic effects and the oral administration were also considered to represent clear advantages for a
population of mainly paediatric patients.

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Overall, the CHMP was of the view that the risks of the product could be considered acceptable if
there were data providing sufficient level of evidence that ataluren may be beneficial in delaying
disease progression in nmDMD. However, considering the totality of data available and the
uncertainties described above, the CHMP concluded that a favourable benefit-risk balance could not
be established at this point.
The applicant applied for a conditional marketing authorisation with the proposal that additional
data would be generated post-authorisation in the confirmatory phase 3 study PTC124-GD-020DMD (Study 020). Therefore, the CHMP also discussed the criteria that would need to be met for a
conditional approval and made the following conclusions:
DMD is a life-threatening and chronically debilitating condition where no satisfactory

methods of treatment exist and it was considered that the product would thus address an unmet
medical need.
The CHMP pointed out that while in case of an orphan condition the clinical dataset might

not be fully comprehensive, the evidence of efficacy should be sufficient to allow assessment and
concluding on a favourable benefit-risk balance. As discussed above, a favourable benefit risk
balance of ataluren was not considered established at this point.
The criterion that the benefits to public health of the immediate availability outweigh the

risks inherent in the fact that additional data are still required was not considered fulfilled since the
benefits to public health were not substantiated by the data presented in the dossier.
With respect to generating additional data post authorisation, the CHMP considered that

the Applicant intends to conduct a confirmatory randomized placebo-controlled Phase 3 study

(Study 020) with the 10, 10, 20 mg/kg/day dose in patients with nmDMD. The CHMP agreed that
this clinical trial may provide data alleviating the current uncertainties, but noted that although it
will presumably be well advanced by the time the product is launched, its conduct (specifically
retention of patients) might be affected by the availability of an authorised product. This impact
was considered specifically in the context of the paediatric setting. Thus, the marketing
authorisation might jeopardise feasibility of completing the study and hence the quality of the
results.
Overall, the CHMP concluded that conditions for granting a conditional marketing authorisation
were not met.
Divergent positions are appended to this report.

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4. Recommendations
Based on the CHMP review of data on quality, safety and efficacy for Translarna in the treatment
of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in
patients aged 5 years and older the CHMP considers by majority decision that the efficacy of the
above mentioned medicinal product is not sufficiently demonstrated and therefore recommends
the refusal of the granting of the conditional Marketing Authorisation for the above mentioned
medicinal product. The CHMP considers that:

The single study fails to demonstrate persuasive evidence of therapeutic efficacy of

Translarna in terms of the primary endpoint (6MWT) and further efficacy parameters confirming
functional improvement and activities of daily living. Furthermore, the mechanism of action and
the bell shape dose-response relationship of Translarna were not conclusively established, which
adds further uncertainty on the overall robustness of the efficacy data.
Therefore, the CHMP was of the opinion that pursuant to Article 12 of Regulation (EC) No
726/2004, the efficacy of the above mentioned medicinal product is not properly or sufficiently
demonstrated.

Furthermore, the CHMP considered that the Applicant has not convincingly shown that

comprehensive data can be obtained from the confirmatory placebo-controlled trial if the product is
authorised and available on the market.
Due to the aforementioned concerns a satisfactory summary of product characteristics, package
leaflet and risk management plan to address other concerns as outlined in the list of outstanding
issues cannot be agreed at this stage.
Furthermore, the CHMP, in light of the negative recommendation, is of the opinion that it is not
appropriate to conclude on the new active substance status at this time.
Divergent positions to the majority recommendation are appended to this report.
Re-examination of the CHMP opinion of 22 May 2014
Following the CHMP conclusion that Translarna was not approvable due to the lack of established
efficacy, the applicant submitted detailed grounds for the re-examination of the grounds for
refusal.
Detailed grounds for re-examination submitted by the applicant
The applicant presented their detailed grounds for re-examination in writing and at an oral
explanation.
A summary of the applicants grounds for re-examination is presented below.
The Applicant requested a re-examination of the CHMP opinion on Translarna, claiming that
substantial evidence is available for granting a conditional marketing authorisation in the following
indication:
Translarna is indicated for the treatment of Duchenne muscular dystrophy resulting from a
nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older.
Efficacy has not been demonstrated in non-ambulatory patients.
The presence of a nonsense mutation in the dystrophin gene should be determined by genetic
testing.

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Overall, the Applicant was of the view that ataluren has a favourable benefit-risk profile in
nmDMD patients, which is a population suffering from a fatal disease with high unmet medical
need, and maintained that criteria for a conditional marketing authorisation were fulfilled.
Ground 1: The single study fails to demonstrate persuasive evidence of therapeutic efficacy of
Translarna in terms of the primary endpoint (6MWT) and further efficacy parameters confirming
functional improvement and activities of daily living. Furthermore, the mechanism of action and
the bell shape dose-response relationship of Translarna were not conclusively established, which
adds further uncertainty on the overall robustness of the efficacy data.
The applicant re-iterated that the ataluren phase 2b study (Study 007) was the first registrationdirected trial in DMD. The lack of an accepted primary endpoint in DMD prior to the conduct of
this study required that the company establish the 6MWT as the primary endpoint, as a result of
which the 6MWT is now an accepted primary outcome measure in DMD clinical trials. In Study
007, the 6MWD results met the MCID for 6MWD in DMD, demonstrating clinical meaningfulness in
a heterogeneous population (estimated 31.7 meters 6MWD benefit over placebo, in the cITT
analysis (post-hoc analysis), adjusted p=0.056). One indication of the robustness of the results
was that slowing of disease progression was also shown in the pre-specified analysis of time to
10%-worsening in 6MWD, in which only 26% of patients who received ataluren 10, 10, 20 mg/kg
experienced disease progression, compared with 44% of the patients who received placebo. The
applicant claimed that the difference between the ataluren 10, 10, 20 mg/kg treatment group and
the placebo group was apparent as early as Week 24 in this analysis.
The applicant highlighted that, given the role of dystrophin in stabilizing muscles and the natural
history of ambulation based on the 6MWT, the effect of ataluren is most evident in patients who
are in the ambulatory decline phase of the disease in a 48-week clinical trial. The eligibility criteria
for the ongoing confirmatory Phase 3 study (study 020) were designed on this basis: age 7 and
16 years; baseline 6MWD 80% of predicted for age and height, (and, to enhance uniformity,
on corticosteroids, and baseline 6MWD 150 meters). Applying these criteria to the Study 007
population, a larger ataluren effect in 6MWD was seen in this decline phase subgroup (49.9
meters, p=0.0096). These data were further supported by the results in patients with more
advanced disease, with baseline 6MWD <350 meters, which indicated a difference for the primary
outcome measure as well as trends favouring ataluren in the TFTs on the lower limb, wheelchair
usage, and the HRQL patient-reported physical function domain.
Furthermore, the robustness of the 6MWT results was in the Applicants view supported by the
positive trends seen in the key secondary endpoints, i.e. TFTs, that represent daily activities and
also predict risk of loss of ambulation. As seen in the 6MWT, the trends in TFTs on the lower limb
were larger in the subgroup enriched for the decline phase than in the overall study population.
The internal consistency of the 6MWD and TFT results was demonstrated in Monte Carlo
simulations, in which 10% of patients were randomly removed from each treatment arm, and the
analysis repeated 1000 separate times. The Monte Carlo analyses and other sensitivity analyses
(such as removal of best/worst patients and the randomization-based ANCOVA analysis)
demonstrated that the results of the study were robust.
Further evidence of the robustness of the data seen was constituted by the positive trends
observed in other secondary endpoints, which pointed in the same direction as the 6MWT and
TFTs: step activity monitoring, wheelchair use, accidental falls, and the QOL child physical
function domain. The results for wheelchair use and the QOL child physical function domain, like
the 6MWT and TFTs, showed larger effect sizes in the subgroup of patients in the ambulatory
decline phase. The totality of the data was considered compelling by the Applicant when looking
at the aggregately positive trends for ataluren vs placebo across outcome measures. With respect
to muscle strength, the applicant pointed out that its measurement is not a relevant outcome for
the evaluation of a dystrophin restoration therapy, making reference to studies using the mdx
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mouse which indicated that dystrophin levels correlate with changes in muscle function but not
with muscle strength.
In terms of dystrophin production, positive differences in dystrophin expression were seen in
ataluren-treated patients in the Phase 2a study. These data were considered by the Applicant to
support the bell-shaped dose response since the majority of patients had plasma concentrations
less than 20 g/ml.

The Applicant acknowledged that those results were not replicated in the

Study 007, giving a variety of reasons, including biopsy sample issues, technical problems, and
shipping and handling-introduced artefacts. Of note, despite considerable technical limitations in
the Phase 2b study, the largest %-increase in dystrophin and the largest number of patients who
exceeded the value of 40% increase were in the 10, 10, 20 mg/kg group, compared to the 20,
20, 40 mg/kg and placebo groups. To put the limited evidence into perspective, the Applicant
made reference to the EMA draft guideline [EMA 2013], specifically to sections recognising that
dystrophin is not a validated biomarker and may provide only complementary information during
diagnosis, and the fact that muscle biopsies are debatable regarding the robustness and the
precise quantification of extremely low levels of dystrophin.
The published in vivo demonstration of atalurens readthrough ability was considered by the
Applicant to be corroborated by the efficacy of ataluren in both the mdx mouse and zebrafish
model of nmDMD. Furthermore, the Applicant documented that atalurens readthrough activity
was thoroughly verified by a number of independent investigators in other disease models (Hurler
syndrome, cystic fibrosis).
With respect to the bell-shaped dose response, several lines of evidence were submitted by the
Applicant in its support, including observations of a bell shaped response in muscle cell cultures
from mdx mice and nmDMD patients, mouse embryonic fibroblasts (MEFs) of nmHurler mice and
in a zebrafish nmDMD model in vivo (sapje mutant).

In addition, the Applicant pointed at

similarities between the ribosomal binding mechanism of ataluren and aminoglycosides, which
also show a bell-shaped response, highlighting that the dose-response relationship is not caused
by adverse effects of ataluren.

Furthermore, the bell-shaped dose-response curve observed in

concentration-based analyses of ataluren in the clinical studies was presented as consistent with
the bell-shaped dose-response hypothesis. In particular, the Applicant presented additional
analyses based on C0h (fig. 17) documenting that the same trend is observed as within the
analyses based on C2h, i.e. higher efficacy in patients with lower concentrations.
Fig. 17 Inverse concentration response C0h data from study 007

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In terms of safety, ataluren was generally well-tolerated by patients with nmDMD at the proposed
recommended dose of 10, 10, 20 mg/kg, as well as at the higher dose of 20, 20, 40 mg/kg, when
taken daily for 48 weeks in the Phase 2b Study 007. The adverse event profile of ataluren was
comparable to that of placebo. Most adverse events were mild or moderate, transient, and did
not require medical intervention. None of the patients discontinued treatment because of adverse
events. Few serious adverse events were reported, none was considered related to ataluren, and
no deaths occurred. Of note, an observational registry study was proposed by the Applicant to
collect additional long-term safety data.
Ground 2: The Applicant has not convincingly shown that comprehensive data can be obtained
from the confirmatory placebo-controlled trial if the product is authorised and available on the
market.
With regard to the completion of the Phase 3 confirmatory trial PTC124-GD-020-DMD (Study
020), the Applicant stated that as of 20 March 2014, 48 study sites were activated, with 163
patients screened and 125 patients randomized. The Applicant committed to completing the study
in a timely manner, allowing availability of results in 3Q 2015. Based on the advanced state of
study enrolment and a careful analysis of when market access to commercial drug would likely
occur in the concerned EU member states, the Applicant was of the view that only a very small
number of patients would be at risk of withdrawing, and maintained that the granting of the
conditional marketing authorisation should not jeopardize the completion or integrity of this
critical study. In this context, the Applicant referred to support from DMD patient advocacy
groups, existing patient-physician relationships and the option of continuing in a separate openlabel extension study as tools encouraging patients to complete the confirmatory trial.
Furthermore, the Applicant argued that the study 020 sample size was sufficiently large to allow
high integrity of conclusions even if some premature patient discontinuations should occur and
also flagged that their successful completion of the study 020 was critical in order to pursue
approval in other regions.
Overall CHMP conclusion on grounds for re-examination
The CHMP assessed all the detailed grounds for re-examination and argumentations presented by
the applicant in writing and in the oral explanation and considered the views expressed by the
Scientific Advisory Group in the initial phase of the procedure.
Ground 1
Following review of the non-clinical evidence available, the CHMP considered that effective
promotion of translation across premature nonsense stop codons was documented in various cell
culture systems as well as in vivo. In particular, the effects of ataluren observed in the zebrafish
sapje mutant and in the different genetic mouse models in vivo were considered of relevance in
terms of the mechanism of action claimed. With respect to the conflicting nature of some of the
results that was pointed out in the initial phase, the CHMP acknowledged that it may be attributed
to methodological differences of the respective assays. Overall, the mechanism of action of
ataluren (nonsense mutation readthrough) was considered plausible. Furthermore, the CHMP
noted that the maximum activity of ataluren in the non-clinical setting was mostly observed at
concentrations overlapping with the efficacious plasma levels of ataluren in the clinical studies
004 and 007, i.e. < 20 g/ml.
The CHMP considered that the activity of ataluren in cultures of myotubes from mdx mice and
nmDMD patients or MEFs of nmHurler mice in vitro and in mutant zebrafish larvae in vivo followed
a bell-shaped dose-response curve. In addition, results in nmHurler mice showed an inverse doseresponse relationship with the lowest dose being most effective, which was also indicative of the
above hypothesis of a bell shape. While some of the previous uncertainties related to the lack of
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verification of the findings by additional non-clinical in vivo data were maintained, overall, the
CHMP concluded that the bell-shaped dose-response could be considered implied by investigations
of atalurens activity in vitro and supported by data from in vivo study in sapje mutant zebrafish,
which constitutes a valuable complement to disease models in mammals.
With respect to clinical evidence of the bell-shaped dose response hypothesis, specific attention
was paid by the CHMP to the re-analyses of the treatment response in correlation to human plasma
concentrations of ataluren. The cut off value of < 19.3 g/ml used for categorization of patients in
low/high plasma level subjects was considered justified, as it was based on the range of C2h seen
in the low dose group (10, 10, 20 mg/kg). The results of this analysis indicated that patients in
study 007 who had lower plasma ataluren concentrations (< 19.3 g/ml) experienced less decline
in 6MWT than patients who had higher plasma ataluren concentrations. Furthermore, in their oral
explanation the Applicant presented additional analysis based on C0h values of plasma
concentration of ataluren, i.e. a parameter which approximately reflects the trough concentration.
Importantly, when looking at the efficacy by concentration, similarly to the observation based on
the C2h data, patients with low concentrations of ataluren performed better than those with high
concentration (both in terms of 6MWD and a across TFTs). Of note, the magnitude of the effect size
observed in patients with lower plasma concentration on the high dose and the one observed in the
patients on the low dose was similar in both instances, i.e. in the analyses based on C0h and C2h
data. This evidence was considered to provide support to the bell-shaped dose-response hypothesis
from the clinical point of view.
Overall, the CHMP was of the view that the bell-shaped dose response hypothesis was plausible
and that despite some limitations of the findings, the available evidence could provide a rationale
for the observed differences in efficacy between the two doses tested, i.e. higher efficacy seen in
the 10, 10, 20 mg/kg dose and minimal efficacy in the 20, 20, 40 mg/kg dose.
In light of the revised position of the CHMP on the mechanism of action and the bell-shaped doseresponse hypothesis, which were both parts of the initial grounds for refusal, the CHMP looked into
the available clinical efficacy data.
The CHMP maintained their initial position that there were limitations of the dataset in terms of
robustness, namely the observation of the variability of the primary efficacy data and the fact that
many of the conclusions supporting efficacy were derived from the post hoc analyses. However,
taking into account that the mechanistic concerns and concerns pertaining to the dose-response
were alleviated during the re-examination, as discussed above, the CHMP was of the view that the
observed results could reflect a true effect. This was considered to adequately reduce the concern
expressed during the initial phase, i.e. that the observed effects could be only chance findings.
With respect to the magnitude and clinical relevance of the observed effects, the CHMP referred to
their previous position, i.e. that there were several lines of evidence supporting the clinical
relevance of a 30-meter difference in 6MWT, including a report showing that a 30-meter change in
6MWD over 48 weeks can be considered a clinically meaningful change based on the
patient/parent-reported quality of life measures in DMD patients. This was also supported by
results of natural history data in DMD, indicating that 30-meter decrease in baseline 6MWD
significantly increases the risk of loss of ambulation over the following 2 years.
As in the initial phase of the MAA review, the CHMP discussed the appropriate target population for
the use of ataluren. Considering that the beneficial effects were most prominent in a subpopulation of ambulatory patients in the decline phase of their walking ability (effect size of
approximately 50 metres on the 6MWD), the CHMP discussed whether this finding would imply the
need for restricting the indication to a population defined accordingly, i.e. patients in ambulatory
decline phase. In line with the previous position of the SAG, the CHMP agreed that scientifically
there should be no reason for the drug not to be given to milder patients if efficacy had been
established in more severe ones. Furthermore, the CHMP considered that while less prominent, a
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clinically meaningful effect was seen also in the overall population studied. Thus, the CHMP
concluded that ataluren can be authorised in the indication that the company claimed in the reexamination:
Translarna is indicated for the treatment of Duchenne muscular dystrophy resulting from a
nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older.
Efficacy has not been demonstrated in non-ambulatory patients.
The presence of a nonsense mutation in the dystrophin gene should be determined by genetic
testing.
Of note, the indication initially applied for, covering also non-ambulatory patients was not pursued
by the Applicant in their Grounds for re-examination. This was considered appropriate by the
CHMP, since ataluren was evaluated only in ambulatory patients.
The CHMP considered that the ground for refusal No. 1 was resolved with a specific obligation to
conduct the confirmatory clinical trial 020. The results of this trial were expected to further reduce
the uncertainties about benefits and support the favourable benefit-risk balance.
Ground 2
The CHMP reviewed the Applicants discussion about the feasibility of the confirmatory trial,
including the progress on recruitment, expected timelines and actions proposed to minimise patient
withdrawals and to ensure successful completion of the trial. Based on the assumptions made by
the Applicant, the CHMP agreed that conducting the confirmatory study 020 and submitting the
final study results by 4Q 2015 could be feasible independently of the status of approval. In
particular, the CHMP took into consideration the additional tools presented by the Applicant to
ensure that patients complete the confirmatory trial. These included existing patient-physician
relationships, the option of continuing participation in a separate open-label extension study and
also support from DMD patient advocacy groups which will be leveraged by the Applicant to
conduct outreach programmes for patients, emphasising the importance of remaining in study 020
through its completion. Furthermore, the CHMP considered that a protocol amendment will be
implemented by the Applicant allowing for additional recruitment, replacing patients who withdraw
from the study for reasons linked to the availability of the product on the market.
The CHMP concluded that the strategy of the Applicant was re-assuring and considered that the
ground for refusal No. 2 was resolved.

Overall conclusion
The Applicant applied for a conditional marketing authorisation with the proposal that additional
data would be generated post-authorisation in the confirmatory phase 3 study (020). Therefore,
the CHMP also re-discussed the criteria that would need to be met for a conditional approval
according to Articles 2 and 4 of the Regulation (EC) no 507/2006, and made the following
conclusions upon re-examination of the initial CHMP Opinion:

DMD is a life-threatening and chronically debilitating condition where no satisfactory

methods of treatment exist and it was considered that the product would thus address an unmet
medical need.

Upon review of the Applicants grounds for re-examination, the CHMP considered that

despite the uncertainties discussed above and the fact that the dataset was not comprehensive,
sufficient efficacy was seen to conclude on a favourable benefit-risk balance. Of note, this
conclusion was to a great extent supported by the safety profile of ataluren, which does not pose
any major safety concerns.

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The criterion that the benefits to public health of the immediate availability outweigh the

risks inherent in the fact that additional data are still required was considered fulfilled since the
benefits to public health were substantiated by providing a treatment for a serious disease,
characterised by gradual deterioration of the condition and a fatal outcome.
With respect to generating additional data post authorisation, the CHMP considered that

the Applicant will complete a confirmatory randomized placebo-controlled Phase 3 study PTC124GD-020-DMD (Study 020) with the 10, 10, 20 mg/kg/day dose in patients with nmDMD. The
CHMP agreed that this clinical trial may provide data alleviating the current uncertainties and
acknowledged the timelines planned for its conduct and submission of its results (4Q 2015). With
respect to the study feasibility, the position of the CHMP changed at the time of the reexamination Opinion; specifically, the CHMP considered that performing the study was plausible
per se, independent of the marketing authorisation status, as discussed above.
A favourable benefit-risk balance was established based on the data available at the time of this
MAA and the CHMP concluded that the confirmatory evidence from study 020 was acceptable to
be generated post authorisation.

4.1. Risk Management Plan

At the end of the initial procedure, the CHMP, having considered the data submitted in the
application was of the opinion that it was not appropriate to consider pharmacovigilance activities
and risk minimisation measures.
During the re-examination procedure, the Applicant addressed the open issues described in the
PRAC RMP assessment dated 03 December 2013. A review of the Applicants responses and of the
updated RMP (submitted as part of the re-examination file) concluded that the RMP in the proposed
treatment of Duchenne muscular dystrophy, resulting from a nonsense mutation in the dystrophin
gene (nmDMD) in ambulatory patients aged 5 years and older, could be acceptable provided that
an updated risk management plan is submitted before final CHMP opinion, addressing the following
issues:
1.

Hepatic toxicity should be included as an important potential risk;

2.

The summary table of risk minimisation measures should be edited to reflect the routine
risk minimisation measures planned for each safety concern (e.g. SmPC);

3.

Amendments are needed in the proposed SmPC to ensure accurate communication on the
monitoring requirements.

Of note, as requested by the PRAC during the initial phase of the MAA procedure, the PASS study
Long-Term Observational Study of Ataluren Safety and Effectiveness in Usual Care was classified
by the Applicant as a category 1 study. With respect to the scope of this PASS study, following a
review of the Applicants responses, it was concluded that it had been satisfactorily expanded to
obtain additional information on the long-term effectiveness of ataluren.
The Applicant addressed the above issues and produced an RMP based on the following content:

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Safety concerns
Summary of safety concerns
Important identified

Potentiation of aminoglycoside renal toxicity

risks

Changes in lipid profile

Important potential

Hypertension with concomitant use of systemic

risks

Missing information

corticosteroids

Renal toxicity

Hepatic toxicity

Hibernoma

Malignancies in general

Effect of co-administration of ataluren with nephrotoxic drugs

other than intravenous aminoglycosides

Use in patients with moderate to severe hepatic impairment

Use in patients with moderate to severe renal impairment

Potential use in children from 6 months to 5 years

Use in patients whose ethnic origin is other than Caucasian

Extended long-term safety

Off-label use in patients who do not have DMD caused by a

nonsense mutation in the dystrophin gene

Effect of co-administration of ataluren with certain drugs not

yet evaluated in formal drug-drug interaction studies

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Pharmacovigilance plans
Study/activity type,
title and category

Objectives

Safety concern
addressed

Post-approval registry

Continue to
document the
long-term safety
profile of
ataluren

Changes in lipid profile

[Working title: LongTerm Observational

Study of Ataluren Safety
and Effectiveness in
Usual Care]
Category 1*

*re-classified to
category 3 at the
request of the CHMP,
see p. 93

Obtain additional
information on
the long-term
effectiveness of
ataluren
Evaluate the
safety and
effectiveness of
ataluren in
subgroups not
traditionally
included in
clinical trials
Evaluate changes
in lipid profile
Determine the
incidence and
frequency of:

o Hypertension

with use of
concomitant
corticosteroids

o Renal toxicity

(without
concomitant
aminoglycosides
or other
nephrotoxic
drugs)

o Hepatic toxicity

Hypertension with use

of concomitant
systemic
corticosteroids
Renal toxicity
Hepatic toxicity
Effect of coadministration of
ataluren with
nephrotoxic drugs
other than intravenous
aminoglycosides
Use in patients with
moderate to severe
hepatic impairment
Use in patients with
moderate to severe
renal impairment

Status
(planned
/started)

Planned

Date for
submission of
interim or final
reports
(planned or
actual)
4Q2015 (1-year
interim)
4Q2016 (2-year
interim)
4Q2017 (3-year
interim)
4Q2018 (4-year
interim)
4Q2019 (5-year
interim)
4Q2020 (6-year
interim)
4Q2021 (7-year
interim)
4Q2022 (final)

Potential use in
children from 6 months
to 5 years
Use in patients whose
ethnic origin is other
than Caucasian
Extended long-term
safety
Off-label use in
patients who do not
have DMD caused by a
nonsense mutation in
the dystrophin gene
Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug interaction
studies

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Study/activity type,
title and category

Objectives

Safety concern
addressed

Status
(planned
/started)

Date for
submission of
interim or final
reports
(planned or
actual)

Potential use in
children from 6 months
to 5 years

Planned

December 2014

Potential use in
children from 6 months
to 5 years

Planned

December 2014

Potential use in
children from 6 months
to 5 years

Planned

December 2014

Evaluate the
safety of
ataluren
in patients with
moderate to
severe renal or
hepatic
impairment
when used with
nephrotoxic
drugs (other
than
aminoglycosides)
Evaluate the
safety and
effectiveness of
ataluren in the
context of
certain
concomitant
drugs
Monitor the
utilization
pattern of
ataluren
7-day tolerability and
pharmacokinetic study
in neonatal dogs
Category 3
1-month juvenile dose
range-finding toxicology
and toxicokinetic study
planned in neonatal
dogs (age correlating
with dosing in newborn
paediatric patients to 2
years of age), Study 2
of
EMA/PDCO/476743/201
2 PDCO document.
Category 3
3-month juvenile
toxicology and
toxicokinetic study
planned in neonatal
dogs (age correlating
with dosing in newborn
paediatric patients to 2
years of age), Study 3
of
EMA/PDCO/476743/201
2 PDCO document
Category 3

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Study/activity type,
title and category

Objectives

Further investigation of
atalurens potential
effect in the
development of
hibernomas

Planned

Date for
submission of
interim or final
reports
(planned or
actual)
December 2014

Further investigation of
atalurens potential
effect in the
development of
hibernomas

Planned

4Q2015

Potential use in
children from 6 months
to 5 years

Planned

December 2016

To evaluate the
safety and PK of
ataluren in
subjects with
different degrees
of hepatic
impairment, in
order to provide
guidance for
ataluren dosing
in patients with
moderate to
severe hepatic
impairment.

Use in patients with

moderate to severe
hepatic impairment

Planned

3Q2017

To evaluate the
safety and PK of
ataluren in
subjects with
different degrees
of renal
impairment, in
order to provide
guidance for
ataluren dosing
in patients with
moderate to
severe renal
impairment.

Use in patients with

moderate to severe
renal impairment

Planned

4Q2017

3 adrenergic binding
assay with ataluren and
the M4 metabolite, if
such a study is
technically feasible

Safety concern
addressed

Status
(planned
/started)

Category 3
Plan to investigate
further postauthorisation the
potential effects of
ataluren and metabolite
M4 in brown adipose
tissue of rats.
Category 3
Open-label safety and
PK study in children age
6 months to 5 years,
Study 6 of
EMA/PDCO/476743/201
2 PDCO document
Category 3
Safety and PK study in
patients with moderate
to severe hepatic
impairment
Category 3

Safety and PK study in

patients with moderate
to severe renal
impairment
Category 3

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Study/activity type,
title and category

Objectives

Safety concern
addressed

Safety and PK study of

co-administration of
ataluren and a sensitive
probe inducer of
UGT1A9

To evaluate the
safety and PK of
ataluren and/or
the appropriate
sensitive probe,
in order to
provide guidance
for dosing
ataluren with the
specific
concomitant
medication.

Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug interaction
studies

Planned

Date for
submission of
interim or final
reports
(planned or
actual)
2Q2015

To evaluate the
safety and PK of
ataluren and/or
the appropriate
sensitive probe
substrate, in
order to provide
guidance for
dosing ataluren
with the specific
concomitant
medication.

Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug interaction
studies

Planned

4Q2015

To evaluate the
safety and PK of
ataluren and/or
the appropriate
sensitive probe,
in order to
provide guidance
for dosing
ataluren with the
specific
concomitant
medication.

Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug interaction
studies

Planned

2Q2016

To evaluate the
safety and PK of
ataluren and/or
the appropriate
sensitive probe
substrate, in
order to provide
guidance for
dosing ataluren
with the specific
concomitant
medication.

Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug interaction
studies

Planned

4Q2016

Category 3

Safety and PK study of

co-administration of
ataluren and a sensitive
probe substrate of
UGT1A9
Category 3

Safety and PK study of

co-administration of
ataluren and a sensitive
probe inhibitor of the
transporter breast
cancer resistant protein
(BCRP)
Category 3

Safety and PK study of

co-administration of
ataluren and a sensitive
probe substrate of
organic anion
transporter 1 (OAT1)
Category 3

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Status
(planned
/started)

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Study/activity type,
title and category

Objectives

Safety concern
addressed

Safety and PK study of

co-administration of
ataluren and a sensitive
probe substrate of
organic anion
transporter 3 (OAT3)

To evaluate the
safety and PK of
ataluren and/or
the appropriate
sensitive probe
substrate, in
order to provide
guidance for
dosing ataluren
with the specific
concomitant
medication.

Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug interaction
studies

Planned

Date for
submission of
interim or final
reports
(planned or
actual)
2Q2017

To evaluate the
safety and PK of
ataluren and/or
the appropriate
sensitive probe
substrate, in
order to provide
guidance for
dosing ataluren
with the specific
concomitant
medication.

Effect of coadministration of
ataluren with certain
drugs not yet
evaluated in formal
drug-drug interaction
studies

Planned

2Q2018

Category 3

Safety and PK study of

co-administration of
ataluren and a sensitive
probe substrate of
organic anion
transporting polypeptide
1B3 (OATP1B3)
Category 3

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Status
(planned
/started)

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Risk minimisation measures

Safety concerns

Routine risk minimisation measures

Potentiation of
aminoglycoside
renal toxicity

SmPC section 4.3 (Contraindications)

Concomitant use of intravenous aminoglycosides (see
section 4.4 and 4.5).

Additional risk
minimisation
measures
None proposed

SmPC section 4.4 (Special warnings and

precautions for use)
Aminoglycosides
Aminoglycosides have been shown to reduce the
readthrough activity of ataluren in vitro. In addition,
ataluren was found to increase nephrotoxicity of
intravenous aminoglycosides. The co-administration of
these medicinal products with ataluren should be
avoided (see section 4.3). Since the mechanism by
which ataluren increases nephrotoxicity of intravenous
aminoglycosides is not known, concomitant use of other
nephrotoxic medicinal products with ataluren is not
recommended. If this is unavoidable (e.g. vancomycin
to treat MRSA) careful monitoring of renal function is
advised (see section 4.5)
SmPC section 4.5 (Interaction with other
medicinal products and other forms of interaction)
Aminoglycosides
Ataluren should not be co-administered with
intravenous aminoglycosides, based on cases of
decreased renal function observed in a clinical trial in
patients with nonsense mutation cystic fibrosis (nmCF)
(see section 4.3).
Elevations of serum creatinine occurred in several nmCF
patients treated with ataluren and intravenous
aminoglycosides together with other antibiotics for
cystic fibrosis exacerbations. The serum creatinine
elevations resolved in all cases, with discontinuation of
the intravenous aminoglycoside, and either continuation
or interruption of Translarna . These findings suggested
that co-administration of Translarna and intravenous
aminoglycosides may potentiate the nephrotoxic effect
of the aminoglycosides. Therefore, if treatment with
intravenous aminoglycosides is necessary the treatment
with Translarna should be stopped and can be resumed
2 days after administration of the aminoglycoside has
ended. The effect of co-administration of ataluren with
other nephrotoxic medicinal products is unknown.
Dehydration may be a contributing factor in some of
these cases. Patients should maintain adequate
hydration while taking ataluren (see section 4.4).

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Safety concerns

Routine risk minimisation measures

Changes in lipid
profile

SmPC section 4.4 Special warnings and

precautions for use
Changes in lipid profile
Because changes in lipid profile (increased
triglycerides and cholesterol) were reported for some
patients in clinical trials, it is recommended that total
cholesterol, LDL, HDL, and triglycerides be monitored
on an annual basis in nmDMD patients receiving
ataluren, or more frequently as needed based on the
patients clinical status.

Additional risk
minimisation
measures
None proposed

SmPC section 4.8 (Undesirable effects)

Change in lipid profile (increased triglycerides and
cholesterol) are included in Table 1.
(Description of selected adverse reactions)
Serum lipids
During the controlled study of nmDMD, mean total
cholesterol and triglycerides were normal at baseline
and increased, reaching borderline high or high values.
The values tended to stabilize early in the study and did
not increase further with continued treatment.
Hypertension with
use of concomitant
corticosteroids

SmPC section 4.4 Special warnings and

precautions for use
Hypertension with use of concomitant systemic
corticosteroids
Because hypertension with use of concomitant
systemic corticosteroids was reported in some
patients in clinical trials, it is recommended that
resting systolic and diastolic blood pressure be
monitored every 6 months in nmDMD patients
receiving ataluren concomitantly with corticosteriods,
or more frequently as needed based on the patients
clinical status.

None proposed

SmPC section 4.8 (Undesirable effects)

Hypertension is included in Table 1.

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Safety concerns

Routine risk minimisation measures

Renal toxicity

SmPC section 4.4 Special warnings and

precautions for use
Renal function monitoring
Because small increases in mean serum creatinine,
blood urea nitrogen (BUN), and cystatin C were
observed in the controlled study of nmDMD, it is
recommended that serum creatinine, BUN, and
cystatin C be monitored every 6 to 12 months in
nmDMD patients receiving ataluren, or more
frequently as needed based on the patients clinical
status.

Additional risk
minimisation
measures
None proposed

SmPC section 4.8 (Undesirable effects)

Change in renal function tests (increased creatinine,
blood urea nitrogen, cystatin C) is included in Table
1.
(Description of selected adverse reactions)
Renal function tests
During the controlled study of nmDMD, small
increases in mean serum creatinine, blood urea
nitrogen (BUN), and cystatin C were observed. The
values tended to stabilize early in the study and did
not increase further with continued treatment.
Hepatic toxicity

None proposed

None proposed

Hibernoma

None proposed

None proposed

Malignancies in
general

None proposed

None proposed

Use of ataluren in
nmDMD patients
who coadministered
ataluren with
nephrotoxic drugs

None proposed
SmPC section 4.4 Special warnings and
precautions for use
Aminoglycosides
Since the mechanism by which ataluren increases
nephrotoxicity of intravenous aminoglycosides is not
known, concomitant use of other nephrotoxic medicinal
products with ataluren is not recommended. If this is
unavoidable (e.g. vancomycin to treat MRSA) careful
monitoring of renal function is advised (see section 4.5).
SmPC section 4.5 (Interaction with other
medicinal products and other forms of interaction)
The effect of co-administration of ataluren with other
nephrotoxic medicinal products is unknown.

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Additional risk
minimisation
measures

Safety concerns

Routine risk minimisation measures

Use of ataluren in
nmDMD patients
with moderate to
severe hepatic
impairment

None proposed
SmPC section 4.2 (Posology and method of
administration)
Renal and hepatic impairment
Safety and efficacy of ataluren in patients with renal and
hepatic impairment have not been established (see
section 4.4).
SmPC section 4.4 Special warnings and
precautions for use)
Hepatic and renal impairment
Patients with renal and hepatic impairments should be
closely monitored.
SmPC section 5.2 Pharmacokinetic properties
Renal or hepatic impairment
No studies have been conducted with Translarna in
patients with renal or hepatic impairment. Patients with
renal or hepatic impairment should be monitored
closely.

Use of ataluren in
nmDMD patients
with moderate to
severe renal
impairment

None proposed
SmPC section 4.2 Posology and method of
administration
Renal and hepatic impairment
Safety and efficacy of ataluren in patients with renal and
hepatic impairment have not been established.
SmPC section 4.4 Special warnings and
precautions for use
Hepatic and renal impairment
Patients with renal and hepatic impairments should be
closely monitored.
SmPC section 5.2 Pharmacokinetic properties
Renal or hepatic impairment
No studies have been conducted with Translarna in
patients with renal or hepatic impairment. Patients with
renal or hepatic impairment should be monitored
closely.

Potential use in
children from 6
months to 5 years
old

None proposed
SmPC section 4.1 (Therapeutic indications)
Translarna is indicated for the treatment of Duchenne
muscular dystrophy resulting from a nonsense mutation
in the dystrophin gene, in ambulatory patients aged 5
years and older.
SmPC section 4.2 (Posology and method of
administration)
The safety and efficacy of Translarna in children and
infants less than 5 years old have not yet been
established.

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Additional risk
minimisation
measures

Safety concerns

Routine risk minimisation measures

Use of ataluren in
patients whose
ethnic origin is
other than
Caucasian

SmPC section 5.2 Pharmacokinetic properties

None proposed
It is unlikely that the pharmacokinetics of ataluren are
significantly affected by UTG1A9 polymorphisms in a
Caucasian population. Due to the low number of other
races included in the clinical studies, no conclusions can
be drawn on the effect of UTG1A9 in other ethnic
groups.

Extended longterm safety

None proposed

None proposed

Off-label use of
ataluren in
patients who do
not have DMD
caused by a
nonsense mutation
in the dystrophin
gene

SmPC section 1 (therapeutic indications)

Translarna is indicated for the treatment of Duchenne
muscular dystrophy resulting from a nonsense mutation
in the dystrophin gene, in ambulatory patients aged 5
years and older. Efficacy has not been demonstrated in
non-ambulatory patients.

None proposed

Effect of coadministration of
ataluren with
certain drugs not
yet evaluated in
formal drug-drug
interaction studies

None proposed
SmPC section 4.4 Special warnings and
precautions for use
Potential interactions with other medicinal products
Caution should be exercised when ataluren is coadministered with medicinal products that are
substrates or inducers of UGT1A9, inhibitors of BCRP, or
substrates of OAT1, OAT3, or OATP1B3 (section 4.5).
SmPC section 4.5 (Interaction with other
medicinal products and other forms of interaction)
Effect of other medicinal products on ataluren
pharmacokinetics
Based on in vitro studies, ataluren is a substrate of
UGT1A9 and breast cancer resistant protein (BCRP).
Caution should be exercised when ataluren is coadministered with medicinal products that are inducers
of UGT1A9 (e.g. mycophenolate mofetil), or inhibitors of
BCRP (e.g. ciclosporin).
Effect of ataluren on pharmacokinetics of other
medicinal products
Based on in vitro studies, ataluren is an inhibitor of
UGT1A9, organic anion transporter 1 (OAT1), organic
anion transporter 3 (OAT3) and organic anion
transporting polypeptide 1B3 (OATP1B3). Caution
should be exercised when ataluren is co-administered
with drugs that are substrates of UGT1A9, OAT1, OAT3,
or OATP1B3 because of the risk of increase
concentration of these medicinal products (eg,
oseltamivir, aciclovir, ciprofloxacin, captopril,
furosemide, bumetanide, valsartan, pravastatin,
rosuvastatin, atorvastatin, pitavastatin).
Based on the in vitro studies, ataluren is not expected
to be an inhibitor of neither p-gp mediated transport nor
of cytochrome P450 mediated metabolism. Similarly,
ataluren is not expected in vivo to be an inducer of
cytochrome P450 isoenzymes.

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The CHMP endorsed the PRAC advice with changes.

These changes concerned the following elements of the Risk Management Plan:
The CHMP considered that the PASS study Long-Term Observational Study of Ataluren Safety and
Effectiveness in Usual Care should be classified as a category 3 study, rather than a category 1
study.
The CHMP justified these changes as follows:
The CHMP considered that the scope of this observational study is to look into the long-term safety
and effectiveness of ataluren, rather than to focus on a specific issue key to the benefit-risk
balance of ataluren.

5. Benefit-Risk Balance
Benefits
Beneficial effects
Ataluren is a first-in-class drug designed to enable ribosomal readthrough of premature stop
codons, resulting in the formation of a full-length functional protein in patients with nonsense
mutation genetic disorders. In the proof of concept study in mdx mice ataluren was seen to
promote formation and adequate localization of dystrophin, resulting in increased muscle strength
and prevention of loss of strength following repeated contractions.
In the clinical setting, beneficial effects of the lower dose (10, 10, 20 mg/kg) were claimed in
both primary and secondary endpoints of physical functioning.
With respect to 6MWD, ataluren was observed to slow disease progression in nmDMD patients.
The post-hoc analysis in the cITT population indicated an estimated difference in the Change in
6MWD at Week 48 of 31.7 metres (nominal p=0.0281, adjusted p=0.0561) between the 10, 10,
20 mg/kg dose and placebo. Looking at the proportions of patients with at least 10% worsening in
6MWD at Week 48, 44% vs 26% of patients in the placebo and the 10, 10, 20 mg/kg ataluren
arm, respectively were progressors (nominal p=0.0326, adjusted p=0.0652) .
A greater effect over 48 weeks was seen in patients in the ambulatory decline phase, i.e.
patients between 7 and 16 years of age, with baseline 6MWD 150m and 80% of predicted
value. Based on a post-hoc subgroup analysis in this population, a difference in the change in
6MWD at Week 48 of 49.9 metres (p=0.0096) between the 10, 10, 20 mg/kg dose and placebo
was seen.
In terms of secondary endpoints of physical functioning, only limited effects of ataluren were
observed: ataluren patients had fewer falls/week than placebo-dosed patients; increase of
wheelchair use from baseline was less in ataluren than placebo; ataluren patients spent less time
in no activity (based on Step activity monitoring) and a minor positive trend was observed in
myometry tests.
Uncertainty in the knowledge about the beneficial effects
The CHMP was of the view that the main uncertainties about the claimed beneficial effects
pertained to the dose-response curve (and hence the appropriate dose), the robustness of
efficacy data in general and the applicability of the data to the overall population of nmDMD
patients.
Uncertainties about the dose-response curve and dose
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The CHMP considered that the activity of ataluren in cultures of myotubes from mdx mice and
nmDMD patients or MEFs of nmHurler mice in vitro and in mutant zebrafish larvae in vivo followed
a bell-shaped dose-response curve. In addition, results in nmHurler mice showed an inverse doseresponse relationship with the lowest dose being most effective, which was also indicative of the
above hypothesis of a bell-shape dose-response. While some of the uncertainties related to the
lack of verification of the findings by additional non-clinical in vivo data were maintained, overall,
the CHMP concluded that the bell-shaped dose-response could be considered implied by
investigations of atalurens activity in vitro and supported by data from in vivo study in sapje
mutant zebrafish, which constitutes a valuable complement to disease models in mammals.
With respect to clinical evidence of the bell-shaped dose response hypothesis, specific attention
was paid by the CHMP to the re-analyses of the treatment response in correlation to human plasma
concentrations of ataluren. The cut off value of < 19.3 g/ml used for categorization of patients in
low/high plasma level subjects was considered justified, as it was based on the range of C2h seen
in the low dose group (10, 10, 20 mg/kg). The results of this analysis indicated that patients in
study 007 who had lower plasma ataluren concentrations (< 19.3 g/ml) experienced less decline
in 6MWT than patients who had higher plasma ataluren concentrations. Furthermore, in their oral
explanation the Applicant presented additional analysis based on C0h values of plasma
concentration of ataluren, i.e. a parameter which approximately reflects the trough concentration.
Importantly, when looking at the efficacy by concentration, similarly to the observation based on
the C2h data, patients with low concentrations of ataluren performed better than those with high
concentration (both in terms of 6MWD and a across TFTs). Of note, the magnitude of the effect size
observed in patients with lower plasma concentration on the high dose and the one observed in the
patients on the low dose was similar in both instances, i.e. in the analyses based on C0h and C2h
data. This evidence was considered to provide support to the bell-shaped dose-response hypothesis
from the clinical point of view.
Uncertainties about robustness of efficacy data
The CHMP was of the view that there were limitations of the dataset in terms of robustness,
namely the observation of the variability of the primary efficacy data and the fact that many of the
conclusions supporting efficacy were derived from the post hoc analyses. However, taking into
account that the mechanistic concerns and concerns pertaining to the dose-response were
alleviated during the re-examination, as discussed above, the CHMP concluded that the observed
results could reflect a true effect. This was considered adequate to reduce the concern expressed
during the initial phase, i.e. that the observed effects could be only chance findings.
The CHMP was of the view that the results on the secondary endpoints provided only limited
support for the primary endpoint outcomes and needed to be seen only as trends. Nevertheless, in
line with the previous input from the SAG, the CHMP acknowledged that most of the secondary
endpoints were of such nature that any effect would have to be driven by an increase in strength
and for this to occur, higher levels of dystrophin in muscular fibres would have to be achieved.
Pharmacodynamic confirmation of efficacy was not provided by the pivotal study, despite the fact
that biopsies were collected. While the technical problems with dystrophin quantification were
recognised by the CHMP, the quality of the biopsies supplied was of concern. The GCP inspection
identified that several steps were underestimated, namely instructions for performing the muscle
biopsies and the storage/ shipping logistics. Since the mechanism of action of ataluren is claimed
to be by promoting production of a full-length dystrophin, more prominent evidence of dystrophin
in muscle of patients treated for 48 weeks would be expected. Considering the limitations of data
on clinical efficacy, the CHMP pointed out that the dossier would have benefited from supportive
data on pharmacodynamics.
With respect to the actual mechanism of restoring dystrophin production, the CHMP considered
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that promotion of the translation process at the ribosomal level was plausible, despite the fact
that positive results were not seen in all assays reported.
Validity of data for the entire nmDMD patient population
Of note, the indication initially applied for, covering also non-ambulatory patients was not pursued
by the Applicant in their Grounds for re-examination. This was considered appropriate by the
CHMP, since ataluren was evaluated only in ambulatory patients.

Risks
Unfavourable effects
Ataluren was generally well tolerated by patients with nmDMD, with the most common adverse
events being headache and gastrointestinal disorders such as nausea, vomiting, (upper)
abdominal pain, flatulence, diarrhoea, stomach discomfort, constipation and regurgitation.
The laboratory data indicated that exposure to ataluren could cause elevation of serum
cholesterol and triglycerides. Mean cholesterol and triglycerides levels were in the upper range of
normal at baseline and increased to borderline-high or high levels in the ataluren arms, primarily
in patients who were receiving corticosteroids. The values tended to stabilize early and did not
increase further with continued treatment. Changes in the lipid profile were considered as an
important identified risk in the proposed Risk Management Plan.
Of note, elevations of serum creatinine occurred in several patients with nonsense mutation cystic
fibrosis treated concomitantly with intravenous aminoglycosides. In all cases, the elevations
resolved with discontinuation of the aminoglycosides indicating that co-administration of ataluren
and intravenous aminoglycosides may potentiate the nephrotoxic effect of the aminoglycosides.
Based on this evidence of decreased renal function, potentiation of aminoglycoside renal toxicity
was determined as an important identified risk.
There were no deaths during the placebo controlled study. Three fatal cases were seen in one
open-label study, but the fatal outcomes were not considered related to treatment with ataluren.
Uncertainty in the knowledge about the unfavourable effects
From the non-clinical database, the finding of malignant hibernomas in rat raised the concern as
to whether occurrence of similar effects could be expected in humans, particularly in the
paediatric population where the quantity of the brown adipose tissue is higher. In particular, the
CHMP considered that malignant hibernomas could be related to the effects of ataluren on fat
tissue metabolism and to effects on plasma lipid parameters, which were observed in rats, dogs
and humans. Thus, hibernomas were reflected in the proposed risk management plan of
ataluren as an important potential risk.
Considering the mechanism of action of ataluren, the CHMP pointed out a theoretical concern
about possible effects of ataluren on reading through normal stop codons (and thus producing
abnormally elongated proteins) and a concern that ataluren could enhance read through of nonsense mutations in other genes. Although such effects were not seen in the data available, the
CHMP was of the view that the potential off-target effects were an uncertainty about the risks of
ataluren.
Based on results of in vitro studies, ataluren was expected to have an interaction potential, which
the CHMP considered necessary to be explored further in vivo. This pertained to ataluren
interactions with a BCRP inhibitor, UGT1A9 substrate, OAT1, OAT3 and OATP1B3 substrates and
UGT1A9 selective inducer.
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Increase in blood pressure including cases of hypertension requiring antihypertensive treatment

was observed in subjects treated with ataluren. While this could have been due to the use of
corticosteroids administered concomitantly, this issue was considered an uncertainty and captured
as a potential risk in the proposed Risk Management Plan.
The preclinical data as well as data from healthy volunteers and DMD patients indicated that
exposure to ataluren may lead to increase in transaminases. While these changes seemed to be
reversible after exposure to ataluren was stopped and a clear hepatotoxic effect was not
confirmed, the CHMP considered hepatotoxicity as an important potential risk.
The nmCF study data suggested an effect of ataluren on renal abnormalities. Although the
mechanism of a potential contribution of ataluren to the reported cases of nephrotoxicity was not
known, this signal in the clinical development appeared to reinforce the non-clinical findings seen
in mice. Based on the clinical data available, renal toxicity was assumed to occur less likely in
DMD patients, but was still perceived as a potential important risk. Of note, data from a clinical
trial investigating ataluren in cystic fibrosis were published at the time of the re-examination
CHMP Opinion (May 2014). Upon request of the CHMP, these results were discussed by the
Applicant in their oral explanation. In their conclusions, the CHMP highlighted that while the
evidence did not indicate increased risk for the DMD population, as a precautionary measure,
additional wording should be implemented in the Product Information to discourage concomitant
use of ataluren and nephrotoxic medicinal products.
Treatment of patients with renal or hepatic impairment is another area of uncertainty, as no
specific

studies

were

performed

and

potential

safety

concerns

are

implied

by

the

pharmacokinetics of ataluren. Since renal excretion accounts for ~ 50% of the drug elimination,
renal impairment is likely to result in accumulation of ataluren and/or ataluren glucuronide.
Similarly, since ataluren is extensively metabolized in liver, hepatic impairment is expected to
result in ataluren increased plasma concentrations. Taken together with the uncertainties around
the claimed bell-shaped dose-response curve, the CHMP considered that without clinical data,
understanding of both efficacy and safety profile of ataluren in subjects with renal or hepatic
impairment remains limited.

Benefit-risk balance
Importance of favourable and unfavourable effects
Several lines of evidence support the clinical relevance of a 30-meter difference in 6MWT,
including a report3 showing that a 30-meter change in 6MWD over 48 weeks can be considered a
clinically meaningful change based on the patient/parent-reported quality of life measures in DMD
patients. This is also supported by results of longitudinal LMWT natural history data in DMD,
indicating that each 30-meter decrease in baseline 6MWD predicts increasing risk of loss of
ambulation over the following 2 years.
Ability to climb and descend a short grouping of stairs, ability to run in short bursts, or to walk a
short distance unaided, e.g. to a bathroom, reflect the typical activities important in the lives of
DMD patients. Importantly, recent data indicated that timed function tests evaluating these
abilities are, similarly to 6MWT, predictive of the time for a patient to become non-ambulatory.
Natural history data from the Cooperative International Neuromuscular Group indicated that
3

Henricson E, Abresch R, Han JJ, Nicorici A, Goude Keller E, de Bie E, McDonald CM. The 6-Minute Walk Test and
Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal
Comparisons and Clinically-Meaningful Changes Over One Year. PLOS Currents Muscular Dystrophy. 2013 Jul 8;
5:ecurrents.md.9e17658b007eb79fcd6f723089f79e06. doi:
10.1371/currents.md.9e17658b007eb79fcd6f723089f79e06
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changes in these parameters are predictive of the likelihood of loss of ambulation over 1 year.
Falls commonly lead to fractures in DMD patients and the injuries sustained may accelerate loss
of ambulation. Decreasing the rate of accidental falls and hence the risk of fractures, pain and
other trauma would be of benefit to the patients. With respect to decrease in wheel chair use,
benefits can be attributed not only in terms of ambulation itself, but also by positive impact on
the respiratory function and minimisation of scoliosis. Thus, if sufficiently documented these
effects would be considered of high importance.
The most commonly reported treatment-related adverse events vomiting, diarrhoea, abdominal
pain upper, flatulence, nausea, headache and decreased appetite were not considered to raise
major safety concerns in a seriously debilitating and life-threatening condition such as DMD.
The effect of ataluren on the lipid profile (cholesterol and triglyceride levels) was considered of
importance, especially in a situation where long-term administration of corticosteroids is
expected. Nevertheless, the values tended to stabilize early in the study and did not increase
further with continued treatment, which was considered re-assuring. Similarly, the risk of
hypertension during concomitant use of corticosteroids and ataluren was seen as of importance to
the target population, considering that such co-administration would occur in the majority of
patients in the clinical practice.
In the context of the age group targeted, the potential risk of hibernoma was considered relevant,
due to higher proportion of brown fat tissue in children.
Discussion on the benefit-risk balance
The CHMP considered that the data presented in the dossier had some deficiencies which impacted
on the benefit-risk assessment. In particular, the Applicant conducted only a single pivotal trial and
with the formal failure of its primary analysis, the efficacy discussion was based on post hoc
analyses. It was agreed that these analyses were performed in line with the most current
knowledge about the natural history of the disease (gained during the conduct of study 007), and
in this respect the definition of the subgroups in these analyses was clinically and scientifically
justified (e.g. patients in decline phase of their ambulation). The effects observed in the pivotal
study were considered generally encouraging, as also supported by the previous input from the
SAG, and in the context of a revised position on the mechanism of action and on the issue of doseresponse relationship, the CHMP was of the view that the observed results could reflect a true
effect and thus constitute evidence of efficacy.
As discussed above, the bell-shape dose response hypothesis was used by the Applicant to explain
why effects were only seen with the lower dose (10, 10, 20 mg/kg). Following re-examination of
the initial opinion the CHMP was of the view that, despite some limitations of the findings, the bellshaped dose response hypothesis was plausible and the available evidence could provide a
rationale for the observed differences in efficacy between the two doses tested, i.e. higher efficacy
seen in the 10, 10, 20 mg/kg dose and minimal efficacy in the 20, 20, 40 mg/kg dose.
The CHMP was of the view that the results on the secondary endpoints provided only limited
support for the primary endpoint outcomes and needed to be seen only as trends. Nevertheless, in
line with the previous input from the SAG, the CHMP acknowledged that most of the secondary
endpoints were of such nature that any effect would have to be driven by an increase in strength
and for this to occur, higher levels of dystrophin in muscular fibres would have to be achieved.
Although the safety data identified some safety concerns, in general these were considered
manageable through the implementation of adequate pharmacovigilance activities and risk
minimisation measures as described in the proposed Risk Management Plan. The lack of serious
toxic effects and the oral administration were also considered to represent clear advantages for a
population of mainly paediatric patients.
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Overall, the CHMP was of the view that the risks of the product could be considered acceptable and
that the data provided sufficient level of evidence that ataluren may be beneficial in delaying
disease progression in nmDMD. Therefore, the CHMP concluded that a favourable benefit-risk
balance could be established at this point.
As in the initial phase of the MAA review, the CHMP discussed the appropriate target population for
the use of ataluren. Considering that the beneficial effects were most prominent in a subpopulation of ambulatory patients in the decline phase of their walking ability (effect size of
approximately 50 metres on the 6MWD), the CHMP discussed whether this finding would imply the
need for restricting the indication to a population defined accordingly, i.e. patients in ambulatory
decline phase. In line with the previous position of the SAG, the CHMP agreed that scientifically
there should be no reason for the drug not to be given to milder patients if efficacy had been
established in more severe ones. Furthermore, the CHMP considered that while less prominent, a
clinically meaningful effect was seen also in the overall population studied. Thus, the CHMP
concluded that ataluren can be authorised in the indication:
Translarna is indicated for the treatment of Duchenne muscular dystrophy resulting from a
nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older.
Efficacy has not been demonstrated in non-ambulatory patients.
The presence of a nonsense mutation in the dystrophin gene should be determined by genetic
testing.
The Applicant applied for a conditional marketing authorisation with the proposal that additional
data would be generated post-authorisation in the confirmatory phase 3 study PTC124-GD-020DMD (study 020). Therefore, the CHMP also re-discussed the criteria that would need to be met for
a conditional approval according to Articles 2 and 4 of the Regulation (EC) no 507/2006, and made
the following conclusions upon re-examination of the initial CHMP Opinion:

DMD is a life-threatening and chronically debilitating condition where no satisfactory

methods of treatment exist and it was considered that the product would thus address an unmet
medical need.

Upon review of the Applicants grounds for re-examination, the CHMP considered that

despite the uncertainties discussed above and the fact that the dataset was not comprehensive,
sufficient efficacy was seen to conclude on a favourable benefit-risk balance. Of note, this
conclusion was to a great extent supported by the safety profile of ataluren, which does not pose
any major safety concerns.

The criterion that the benefits to public health of the immediate availability outweigh the

risks inherent in the fact that additional data are still required was considered fulfilled since the
benefits to public health were substantiated by providing a treatment for a serious disease,
characterised by gradual deterioration of the condition and a fatal outcome.

With respect to generating additional data post authorisation, the CHMP considered that

the Applicant will complete a confirmatory randomized placebo-controlled Phase 3 study (study
020) with the 10, 10, 20 mg/kg/day dose in patients with nmDMD. The CHMP agreed that this
clinical trial may provide data alleviating the current uncertainties and acknowledged the timelines
planned for its conduct and submission of its results (4Q 2015). With respect to the study
feasibility, the position of the CHMP changed at the time of the re-examination Opinion;
specifically, the CHMP considered that performing the study was plausible per se, independent of
the marketing authorisation status.
A favourable benefit-risk balance was established based on the data available at the time of this
MAA and the CHMP concluded that the confirmatory evidence from study 020 was acceptable to
be generated post authorisation.
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Overall, the CHMP concluded that conditions for granting a conditional marketing authorisation
were met.
Recommendations following re-examination
Based on the arguments of the applicant and all the supporting data on quality, safety and efficacy,
the CHMP re-examined its initial opinion and in its final opinion concluded by majority decision that
the risk-benefit balance of Translarna indicated for
Translarna is indicated for the treatment of Duchenne muscular dystrophy resulting from a
nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older.
Efficacy has not been demonstrated in non-ambulatory patients.
The presence of a nonsense mutation in the dystrophin gene should be determined by genetic
testing.
is favourable and therefore recommends the granting of the conditional marketing authorisation
subject to the following conditions:

Conditions or restrictions regarding supply and use

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).

Other conditions and requirements of the Marketing Authorisation

Periodic Safety Update Reports

The marketing authorisation holder shall submit the first periodic safety update report for this
product within 6 months following authorisation. Subsequently, the marketing authorisation holder
shall submit periodic safety update reports for this product in accordance with the requirements set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and published on the European medicines web-portal.

Conditions or restrictions with regard to the safe and effective use of the
medicinal product

Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent
updates of the RMP.
An updated RMP should be submitted:

At the request of the European Medicines Agency;

Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile
or as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at
the same time.

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Specific Obligation to complete post-authorisation measures for the

conditional marketing authorisation
This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC)
No 726/2004, the MAH shall complete, within the stated timeframe, the following measures:
Description
To

complete

Due date
a

multicentre,

randomised,

double-blind,

placebo-controlled

Submission

confirmatory study to examine efficacy and safety of ataluren 10, 10, 20 mg/kg

of

in patients with non-sense mutation Duchenne muscular dystrophy (Study

report:

the

final

PTC124-GD-020-DMD)

By 4Q 2015

Conditions or restrictions with regard to the safe and effective use of the
medicinal product to be implemented by the Member States
Not applicable.

New Active Substance Status

Based on the CHMP review of data on the quality properties of the active substance, the CHMP
considers that ataluren is qualified as a new active substance.

Divergent positions to the majority recommendation are appended to this report.

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DIVERGENT POSITION DATED 23 JANUARY 2014

The undersigned members of the CHMP did not agree with the CHMPs negative opinion
recommending the refusal of the granting of a conditional approval of Translarna in the indication
treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin
gene, in patients aged 5 years and older.
The reasons for the divergent opinion are as follows:
Translarna was developed to address the unmet medical need of the small fraction of patients with
Duchenne muscular dystrophy (DMD) caused by a nonsense mutation, estimated to be 2500
patients (13%) of the European DMD population (~19000 patients). There are no remaining issues
from the Quality point of view, and although some Non-clinical issues are still identified, they can
be followed-up post approval. Considering the Clinical data, although the results are not sufficiently
robust for a full Marketing Authorisation, the demonstrated effects are considered to be
encouraging. The robustness of the results was challenged because of the observed variability in
the primary efficacy data, the fact that many of the important conclusions supporting efficacy were
derived from post hoc analyses and the fact that there was little supportive evidence of effect from
the data on the secondary endpoints. It is recognized that at the time the study was designed the
knowledge of the natural history of the disease was different from what we currently know.
Therefore, the post hoc analyses reflecting the most current knowledge about the natural history of
the disease, and in this respect the definition of the sub-groups in these analyses is clinically and
scientifically justified. In agreement with the SAG experts, results derived from these analyses may
be considered clinically relevant, especially in the sub-group of patients with more advanced
disease. Additionally, the lack of effect on the secondary endpoints could be explained by the
expected mechanism of action of the drug i.e. partial restoration of dystrophin production. Most of
the secondary endpoints are of such nature that any effect will have to be driven by an increase in
strength, rather than by an improvement of function. The latest available data suggest that
minimal increase in dystrophin production could lead to functional improvement, but not to
improvement of strength. For the latter to occur, levels of dystrophin close to the ones in normal
muscular fibres may need to be achieved. This could be a valid explanation of the lack of
concordance between the results on the primary and secondary efficacy endpoints. The group also
noted that, despite the fact that efficacy was most prominently shown in the sub-group of patients
with more advanced disease, there were trends of efficacy in all the sub-groups by severity,
although of a different magnitude. This finding may be expected since the decline in function of
DMD patients is not linear, but rather the speed of functional decline increases with the duration of
the disease. In that respect, it would be very difficult to show a significant functional improvement
in mildly affected patients in the frame of a controlled clinical trial with duration of 1 or 2 years. On
the contrary, in more severely affected patients even a small effect on function could be detectable
and clinically meaningful. It should be acknowledged that, in these patients, even small effects
providing longer independent use of arms and hands, or preserving the ability to feed and drink
from a cup on their own, would represent a significant and important achievement.
Taking all of the above into consideration and in the absence of major safety concerns, the
minority view was that a positive benefit/risk relationship of ataluren has been reasonably
established in Duchenne patients with nonsense mutations and, consequently, treatment with
ataluren should not be withheld from these patients. A conditional approval with the ongoing phase

III trial as condition was considered acceptable. In addition, the long-term benefit of ataluren in
this population could be documented by following patients up in specific registries.
Overall, and under the scope of a conditional approval, the B/R balance is considered to be positive
in the following indication: Duchenne muscular dystrophy (nmDMD) caused by nonsense mutation
in the dystrophin gene, in ambulatory patients aged 5 and older.
London, 23 January 2014
Jan Mueller-Berghaus

Bruno Sepodes

Jean-Louis Robert

Natalja Karpova

Jan Mazag

Daniela Melchiorri

Jens Heisterberg

Pierre Demolis

Harald Enzmann

Jacqueline Genoux-Hames

DIVERGENT POSITION DATED 22 MAY 2014

The undersigned member(s) of the CHMP did not agree with the CHMPs positive opinion
recommending the granting of the marketing authorisation of Translarna indicated in the treatment
of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in
ambulatory patients aged 5 years and older.

The reason for the divergent opinion was as follows:

The single study fails to demonstrate evidence of therapeutic efficacy of Translarna either
on the primary endpoint (6MWD) or on secondary efficacy measures. The study failed on
its primary endpoint analysis and efficacy claims are based on post hoc revisions to the
analysis and on subgroup analyses. The argument that efficacy could be shown more easily
in the decline phase subgroup seems plausible, based on data on the natural history of the
disease, and it is agreed that confirmation of efficacy in these patients could be in principle
extrapolated to support a general indication in DMD. However there are concerns that the
presented analyses in this subgroup might be data driven i.e. the inclusion or exclusion
from the subgroup of a few patients with a large change in 6MWD (depending on how the
population is defined) could substantially affect the analysis. In this context it is noted that
the corresponding analysis in the pre-specified <350 metre (baseline 6MWD) subgroup was
much less impressive than in the post hoc defined decline phase subgroup. The mechanism
of action of Translarna and an effect on a relevant pharmacodynamic measure have not
been conclusively established, which adds further uncertainty. There is some evidence for
the bell shape dose-response relationship but still some uncertainty. The numerous
assumptions that need to be made to accept the claim that efficacy is shown for the low
dose (but not the high dose) in the decline phase subgroup is considered problematic.
Confirmatory data from on-going phase 3 trial are considered necessary and a positive
benefit-risk balance has not been established at the present time due to a lack of evidence
of efficacy.

London, 22 May 2014

Nela Vilceanu

Alar Irs

Karsten Bruins Slot

Sol Ruiz

Robert Hemmings

Ondrej Slanar

Daniel Brasseur

David Lyons

Greg Markey

Dinah Duarte

Pieter de Graeff

Concepcion Prieto Yerro

Reynir Arngrimsson

Romaldas Maciulaitis